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Ercanbrack WS, Ramirez M, Dungan A, Gaul E, Ercanbrack SJ, Wingert RA. Frataxin deficiency and the pathology of Friedreich's Ataxia across tissues. Tissue Barriers 2025:2462357. [PMID: 39981684 DOI: 10.1080/21688370.2025.2462357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 01/08/2025] [Accepted: 01/14/2025] [Indexed: 02/22/2025] Open
Abstract
Friedreich's Ataxia (FRDA) is a neurodegenerative disease that affects a variety of different organ systems. The disease is caused by GAA repeat expansions in intron 1 of the Frataxin gene (FXN), which results in a decrease in the expression of the FXN protein. FXN is needed for the biogenesis of iron-sulfur clusters (ISC) which are required by key metabolic processes in the mitochondria. Without ISCs those processes do not occur properly. As a result, reactive oxygen species accumulate, and the mitochondria cease to function. Iron is also thought to accumulate in the cells of certain tissue types. These processes are thought to be intimately related to the pathologies affecting a myriad of tissues in FRDA. Most FRDA patients suffer from loss of motor control, cardiomyopathy, scoliosis, foot deformities, and diabetes. In this review, we discuss the known features of FRDA pathology and the current understanding about the basis of these alterations.
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Affiliation(s)
- Wesley S Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Mateo Ramirez
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Austin Dungan
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Ella Gaul
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Sarah J Ercanbrack
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA
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Lynch DR, Shen M, Wilson RB. Friedreich ataxia: what can we learn from non-GAA repeat mutations? Neurodegener Dis Manag 2025; 15:17-26. [PMID: 39810561 PMCID: PMC11938963 DOI: 10.1080/17582024.2025.2452147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 01/08/2025] [Indexed: 01/16/2025] Open
Abstract
Friedreich ataxia (FRDA) is a slowly progressive neurological disease resulting from decreased levels of the protein frataxin, a small mitochondrial protein that facilitates the synthesis of iron-sulfur clusters in the mitochondrion. It is caused by GAA (guanine-adenine-adenine) repeat expansions in the FXN gene in 96% of patients, with 4% of patients carrying other mutations (missense, nonsense, deletion) in the FXN gene. Compound heterozygote patients with one expanded GAA allele and a non-GAA repeat mutation can have subtle differences in phenotype from typical FRDA, including, in patients with selected missense mutations, both more severe features and less severe features in the same patient. In this review, we propose explanations for such phenotypes based on the potential for activities of frataxin other than enhancement of iron-sulfur cluster synthesis, as well as crucial future experiments for fully understanding the role of frataxin in cells.
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Affiliation(s)
- David R. Lynch
- Friedreich Ataxia Program, Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
- Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| | - M. Shen
- Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
| | - Robert B. Wilson
- Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
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Tamaroff J, Nguyen S, Wilson NE, Stefanovski D, Xiao R, Scattergood T, Capiola C, Schur GM, Dunn J, Dedio A, Wade K, Shah H, Sharma R, Mootha VK, Kelly A, Lin KY, Lynch DR, Reddy R, Rickels MR, McCormack SE. Insulin Sensitivity and Insulin Secretion in Adults With Friedreich's Ataxia: The Role of Skeletal Muscle. J Clin Endocrinol Metab 2025; 110:317-333. [PMID: 39109797 PMCID: PMC11747682 DOI: 10.1210/clinem/dgae545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 07/28/2024] [Accepted: 08/05/2024] [Indexed: 09/12/2024]
Abstract
INTRODUCTION Friedreich's ataxia (FRDA) is a multisystem disorder caused by frataxin deficiency. FRDA-related diabetes mellitus (DM) is common. Frataxin supports skeletal muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity, a mediator of insulin sensitivity. Our objective was to test the association between skeletal muscle health and insulin sensitivity and secretion in adults with FRDA without DM. METHODS Case-control study (NCT02920671). Glucose and insulin metabolism (stable-isotope oral glucose tolerance tests), body composition (dual-energy x-ray absorptiometry), physical activity (self-report), and skeletal muscle OXPHOS capacity (creatine chemical exchange saturation transfer magnetic resonance imaging) were assessed. RESULTS Participants included 11 individuals with FRDA (4 female), median age 27 years (interquartile range 23, 39), body mass index 26.9 kg/m2 (24.1, 29.4), and 24 controls (11 female), 29 years (26, 39), 24.4 kg/m2 (21.8, 27.0). Fasting glucose was higher in FRDA [91 vs 83 mg/dL (5.0 vs 4.6 mmol/L), P < .05]. Individuals with FRDA had lower insulin sensitivity (whole-body insulin sensitivity index 2.8 vs 5.3, P < .01), higher postprandial insulin secretion (insulin secretory rate incremental area under the curve 30-180 minutes, 24 652 vs 17,858, P < .05), and more suppressed postprandial endogenous glucose production (-.9% vs 26.9% of fasting endogenous glucose production, P < .05). In regression analyses, lower OXPHOS and inactivity explained some of the difference in insulin sensitivity. More visceral fat contributed to lower insulin sensitivity independent of FRDA. Insulin secretion accounting for sensitivity (disposition index) was not different. CONCLUSION Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory and, when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.
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Affiliation(s)
- Jaclyn Tamaroff
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Division of Pediatric Endocrinology and Diabetes, Vanderbilt University Medical Center, Nashville, TN 37232, USA
| | - Sara Nguyen
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Neil E Wilson
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Darko Stefanovski
- New Bolton Center, University of Pennsylvania School of Veterinary Medicine, Kennett Square, PA 19348, USA
| | - Rui Xiao
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Theresa Scattergood
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Christopher Capiola
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Gayatri Maria Schur
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Medical Scientist Training Program, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Julia Dunn
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Anna Dedio
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Kristin Wade
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Hardik Shah
- Department of Molecular Biology, Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute, Cambridge, MA 02142, USA
- Metabolomics Platform, Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA
| | - Rohit Sharma
- Department of Molecular Biology, Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute, Cambridge, MA 02142, USA
| | - Vamsi K Mootha
- Department of Molecular Biology, Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
- Broad Institute, Cambridge, MA 02142, USA
| | - Andrea Kelly
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kimberly Y Lin
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Division of Pediatric Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - David R Lynch
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Ravinder Reddy
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michael R Rickels
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Shana E McCormack
- Division of Pediatric Endocrinology and Diabetes, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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Lischewski SA, Konrad K, Dogan I, Didszun C, Costa AS, Schawohl SA, Giunti P, Parkinson MH, Mariotti C, Nanetti L, Durr A, Ewenczyk C, Boesch S, Nachbauer W, Klopstock T, Stendel C, de Rivera Garrido FJR, Schöls L, Fleszar Z, Klockgether T, Grobe‐Einsler M, Giordano I, Rai M, Pandolfo M, Schulz JB, Reetz K. Longitudinal analysis of anthropometric measures over 5 years in patients with Friedreich ataxia in the EFACTS natural history study. Eur J Neurol 2025; 32:e70011. [PMID: 39797559 PMCID: PMC11724196 DOI: 10.1111/ene.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 12/06/2024] [Indexed: 01/13/2025]
Abstract
BACKGROUND Friedreich ataxia is a rare neurodegenerative disorder caused by frataxin deficiency. Both underweight and overweight occur in mitochondrial disorders, each with adverse health outcomes. We investigated the longitudinal evolution of anthropometric abnormalities in Friedreich ataxia and the hypothesis that both weight loss and weight gain are associated with faster disease progression. METHODS Participants were drawn from the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS). Age- and sex-specific BMI and height scores were calculated using the KIGGS-BMI percentiles for children. Height correction was applied for scoliosis. Longitudinal data were analysed using linear mixed effects models and incremental standard deviation scores and growth mixture models identified subclasses with varying BMI trajectories. RESULTS Five hundred and forty-three adults and fifty-nine children were assessed for up to 5 years. In children, severe underweight (26%), underweight (7%), severe short stature (16%) and short stature (23%) were common. The corrected BMI percentile was stable in children, although 48% had negative incremental BMI scores over 1 year and 63% over 3 years versus 10%/year in a normal reference cohort. Overweight was common in adults (19%), with a slight increase in BMI over time. Longer GAA repeat size was linked to lower BMI in adults. Weight trajectory was not associated with ataxia progression in adults. CONCLUSION Significant anthropometric abnormalities were identified, with underweight and short stature prevalent in children and overweight in adults. These findings highlight the need for regular nutritional monitoring and interventions to manage underweight in children and promote healthy weight in adults.
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Affiliation(s)
| | - Kerstin Konrad
- JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbHJülichGermany
- Child Neuropsychology Section, Department of Child and Adolescent Psychiatry, Psychosomatics and PsychotherapyUniversity Hospital, RWTHAachenGermany
| | - Imis Dogan
- Department of NeurologyRWTH Aachen UniversityAachenGermany
| | - Claire Didszun
- Department of NeurologyRWTH Aachen UniversityAachenGermany
| | - Ana Sofia Costa
- Department of NeurologyRWTH Aachen UniversityAachenGermany
- JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbHJülichGermany
| | | | - Paola Giunti
- Ataxia Centre, Department of Clinical and Movement NeurosciencesUCL‐Queen Square Institute of NeurologyLondonUK
| | - Michael H. Parkinson
- Ataxia Centre, Department of Clinical and Movement NeurosciencesUCL‐Queen Square Institute of NeurologyLondonUK
| | - Caterina Mariotti
- Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
| | - Lorenzo Nanetti
- Unit of Medical Genetics and NeurogeneticsFondazione IRCCS Istituto Neurologico Carlo BestaMilanItaly
| | - Alexandra Durr
- Paris Brain Institute, ICM Institut du Cerveau, AP‐HP, INSERM, CNRS, University Hospital Pitié‐Salpêtrière, Sorbonne UniversiteParisFrance
| | - Claire Ewenczyk
- Paris Brain Institute, ICM Institut du Cerveau, AP‐HP, INSERM, CNRS, University Hospital Pitié‐Salpêtrière, Sorbonne UniversiteParisFrance
| | - Sylvia Boesch
- Department of NeurologyMedical University InnsbruckInnsbruckAustria
| | | | - Thomas Klopstock
- Department of NeurologyFriedrich Baur Institute, University Hospital, LMUMunichGermany
- German Center for Neurodegenerative DiseasesMunichGermany
- Munich Cluster for Systems NeurologyMunichGermany
| | - Claudia Stendel
- Department of NeurologyFriedrich Baur Institute, University Hospital, LMUMunichGermany
- German Center for Neurodegenerative DiseasesMunichGermany
| | | | - Ludger Schöls
- Department of Neurology and Hertie‐Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
- German Center for Neurodegenerative DiseasesTübingenGermany
| | - Zofia Fleszar
- Department of Neurology and Hertie‐Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
- German Center for Neurodegenerative DiseasesTübingenGermany
| | - Thomas Klockgether
- Department of NeurologyUniversity Hospital of BonnBonnGermany
- German Center for Neurodegenerative DiseasesBonnGermany
| | - Marcus Grobe‐Einsler
- Department of NeurologyUniversity Hospital of BonnBonnGermany
- German Center for Neurodegenerative DiseasesBonnGermany
| | - Ilaria Giordano
- Department of NeurologyUniversity Hospital of BonnBonnGermany
| | - Myriam Rai
- Friedreich Ataxia Research AllianceDowningtownPennsylvaniaUSA
| | - Massimo Pandolfo
- Laboratory of Experimental NeurologyUniversité Libre de BruxellesBrusselsBelgium
| | - Jörg B. Schulz
- Department of NeurologyRWTH Aachen UniversityAachenGermany
- JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbHJülichGermany
| | - Kathrin Reetz
- Department of NeurologyRWTH Aachen UniversityAachenGermany
- JARA‐BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbHJülichGermany
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Mosbach V, Puccio H. A multiple animal and cellular models approach to study frataxin deficiency in Friedreich Ataxia. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119809. [PMID: 39134123 DOI: 10.1016/j.bbamcr.2024.119809] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 08/01/2024] [Accepted: 08/02/2024] [Indexed: 08/15/2024]
Abstract
Friedreich's ataxia (FA) is one of the most frequent inherited recessive ataxias characterized by a progressive sensory and spinocerebellar ataxia. The main causative mutation is a GAA repeat expansion in the first intron of the frataxin (FXN) gene which leads to a transcriptional silencing of the gene resulting in a deficit in FXN protein. The nature of the mutation (an unstable GAA expansion), as well as the multi-systemic nature of the disease (with neural and non-neural sites affected) make the generation of models for Friedreich's ataxia quite challenging. Over the years, several cellular and animal models for FA have been developed. These models are all complementary and possess their own strengths to investigate different aspects of the disease, such as the epigenetics of the locus or the pathophysiology of the disease, as well as being used to developed novel therapeutic approaches. This review will explore the recent advancements in the different mammalian models developed for FA.
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Affiliation(s)
- Valentine Mosbach
- Institut NeuroMyoGene-PGNM UCBL-CNRS UMR5261 INSERM U1315, Lyon, France
| | - Hélène Puccio
- Institut NeuroMyoGene-PGNM UCBL-CNRS UMR5261 INSERM U1315, Lyon, France.
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Wu L, Huang F, Yang L, Yang L, Sun Z, Zhang J, Xia S, Zhao H, Ding Y, Bian D, Li K. Interplay of FXN expression and lipolysis in white adipocytes plays a critical role in insulin sensitivity in Friedreich's ataxia mouse model. Sci Rep 2024; 14:19876. [PMID: 39191875 DOI: 10.1038/s41598-024-71099-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/23/2024] [Indexed: 08/29/2024] Open
Abstract
Frataxin (FXN) is required for iron-sulfur cluster biogenesis, and its loss causes the early-onset neurodegenerative disease Friedreich ataxia (FRDA). Loss of FXN is a susceptibility factor in the development of diabetes, a common metabolic complication after myocardial hypertrophy in patients with FRDA. The underlying mechanism of FXN deficient-induced hyperglycemia in FRDA is, however, poorly understood. In this study, we confirmed that the FXN deficiency mouse model YG8R develops insulin resistance in elder individuals by disturbing lipid metabolic homeostasis in adipose tissues. Evaluation of lipolysis, lipogenesis, and fatty acid β-oxidation showed that lipolysis is most severely affected in white adipose tissues. Consistently, FXN deficiency significantly decreased expression of lipolytic genes encoding adipose triglyceride lipase (Atgl) and hormone-sensitive lipase (Hsl) resulting in adipocyte enlargement and inflammation. Lipolysis induction by fasting or cold exposure remarkably upregulated FXN expression, though FXN deficiency lessened the competency of lipolysis compared with the control or wild type mice. Moreover, we found that the impairment of lipolysis was present at a young age, a few months earlier than hyperglycemia and insulin resistance. Forskolin, an activator of lipolysis, or pioglitazone, an agonist of PPARγ, improved insulin sensitivity in FXN-deficient adipocytes or mice. We uncovered the interplay between FXN expression and lipolysis and found that impairment of lipolysis, particularly the white adipocytes, is an early event, likely, as a primary cause for insulin resistance in FRDA patients at later age.
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Affiliation(s)
- Lin Wu
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Fei Huang
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Lu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Liu Yang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Zichen Sun
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Jinghua Zhang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Siyu Xia
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China
| | - Hongting Zhao
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Yibing Ding
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China
| | - Dezhi Bian
- Endocrinology Department, Yancheng First People's Hospital, Affiliated Hospital of Medical School, Nanjing University, Yancheng, 224000, People's Republic of China.
| | - Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
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Cai Z, Yang Y, Zhong J, Ji Y, Li T, Luo J, Hu S, Luo H, Wu Y, Liu F, Zhang J. cGAS suppresses β-cell proliferation by a STING-independent but CEBPβ-dependent mechanism. Metabolism 2024; 157:155933. [PMID: 38729601 DOI: 10.1016/j.metabol.2024.155933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 04/21/2024] [Accepted: 05/05/2024] [Indexed: 05/12/2024]
Abstract
AIMS/HYPOTHESIS cGAS (cyclic GMP-AMP synthase) has been implicated in various cellular processes, but its role in β-cell proliferation and diabetes is not fully understood. This study investigates the impact of cGAS on β-cell proliferation, particularly in the context of diabetes. METHODS Utilizing mouse models, including cGAS and STING (stimulator of interferon genes) knockout mice, we explored the role of cGAS in β-cell function. This involved β-cell-specific cGAS knockout (cGASβKO) mice, created by breeding cGAS floxed mice with transgenic mice expressing Cre recombinase under the insulin II promoter. We analyzed cGAS expression in diabetic mouse models, evaluated the effects of cGAS deficiency on glucose tolerance, and investigated the molecular mechanisms underlying these effects through RNA sequencing. RESULTS cGAS expression is upregulated in the islets of diabetic mice and by high glucose treatment in MIN6 cells. Both global cGAS deficiency and β-cell-specific cGAS knockout mice lead to improved glucose tolerance by promoting β-cell mass. Interestingly, STING knockout did not affect pancreatic β-cell mass, suggesting a STING-independent mechanism for cGAS's role in β-cells. Further analyses revealed that cGAS- but not STING-deficiency leads to reduced expression of CEBPβ, a known suppressor of β-cell proliferation, concurrently with increased β-cell proliferation. Moreover, overexpression of CEBPβ reverses the upregulation of Cyclin D1 and D2 induced by cGAS deficiency, thereby regulating β-cell proliferation. These results confirm that cGAS regulation of β-cell proliferation via a CEBPβ-dependent but STING-independent mechanism. CONCLUSIONS/INTERPRETATION Our findings highlight the pivotal role of cGAS in promoting β-cell proliferation and maintaining glucose homeostasis, potentially by regulating CEBPβ expression in a STING-independent manner. This study uncovers the significance of cGAS in controlling β-cell mass and identifies a potential therapeutic target for enhancing β-cell proliferation in the treatment of diabetes.
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Affiliation(s)
- Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yan Yang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jiaxin Zhong
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yujiao Ji
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ting Li
- Departments of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Jing Luo
- Departments of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shanbiao Hu
- Departments of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yan Wu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Feng Liu
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Cardiometabolic Medicine of Hunan Province, Metabolic Syndrome Research Center, Department of Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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8
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Turchi R, Sciarretta F, Ceci V, Tiberi M, Audano M, Pedretti S, Panebianco C, Nesci V, Pazienza V, Ferri A, Carotti S, Chiurchiù V, Mitro N, Lettieri-Barbato D, Aquilano K. Butyrate prevents visceral adipose tissue inflammation and metabolic alterations in a Friedreich's ataxia mouse model. iScience 2023; 26:107713. [PMID: 37701569 PMCID: PMC10494209 DOI: 10.1016/j.isci.2023.107713] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 08/02/2023] [Accepted: 08/23/2023] [Indexed: 09/14/2023] Open
Abstract
Friedreich's ataxia (FA) is a neurodegenerative disease resulting from a mutation in the FXN gene, leading to mitochondrial frataxin deficiency. FA patients exhibit increased visceral adiposity, inflammation, and heightened diabetes risk, negatively affecting prognosis. We investigated visceral white adipose tissue (vWAT) in a murine model (KIKO) to understand its role in FA-related metabolic complications. RNA-seq analysis revealed altered expression of inflammation, angiogenesis, and fibrosis genes. Diabetes-like traits, including larger adipocytes, immune cell infiltration, and increased lactate production, were observed in vWAT. FXN downregulation in cultured adipocytes mirrored vWAT diabetes-like features, showing metabolic shifts toward glycolysis and lactate production. Metagenomic analysis indicated a reduction in fecal butyrate-producing bacteria, known to exert antidiabetic effects. A butyrate-enriched diet restrained vWAT abnormalities and mitigated diabetes features in KIKO mice. Our work emphasizes the role of vWAT in FA-related metabolic issues and suggests butyrate as a safe and promising adjunct for FA management.
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Affiliation(s)
- Riccardo Turchi
- Department Biology, University of Rome Tor Vergata, Rome, Italy
| | | | - Veronica Ceci
- PhD Program in Evolutionary Biology and Ecology, Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Marta Tiberi
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Matteo Audano
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Silvia Pedretti
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Concetta Panebianco
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Valentina Nesci
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Valerio Pazienza
- Gastroenterology Unit Fondazione IRCSS “Casa Sollievo della Sofferenza” Hospital San Giovanni Rotondo (FG)-Italy
| | - Alberto Ferri
- Division of Experimental Neuroscience, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
- Predictive Molecular Diagnostics, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Valerio Chiurchiù
- Laboratory of Resolution of Neuroinflammation, IRCCS Fondazione Santa Lucia, Rome, Italy
- Institute of Traslational Pharmacology, IFT-CNR, Rome, Italy
| | - Nico Mitro
- DiSFeB, Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Daniele Lettieri-Barbato
- Department Biology, University of Rome Tor Vergata, Rome, Italy
- IRCCS Fondazione Santa Lucia, Rome, Italy
| | - Katia Aquilano
- Department Biology, University of Rome Tor Vergata, Rome, Italy
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9
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Maheshwari S, Vilema-Enríquez G, Wade-Martins R. Patient-derived iPSC models of Friedreich ataxia: a new frontier for understanding disease mechanisms and therapeutic application. Transl Neurodegener 2023; 12:45. [PMID: 37726850 PMCID: PMC10510273 DOI: 10.1186/s40035-023-00376-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/28/2023] [Indexed: 09/21/2023] Open
Abstract
Friedreich ataxia (FRDA) is a rare genetic multisystem disorder caused by a pathological GAA trinucleotide repeat expansion in the FXN gene. The numerous drawbacks of historical cellular and rodent models of FRDA have caused difficulty in performing effective mechanistic and translational studies to investigate the disease. The recent discovery and subsequent development of induced pluripotent stem cell (iPSC) technology provides an exciting platform to enable enhanced disease modelling for studies of rare genetic diseases. Utilising iPSCs, researchers have created phenotypically relevant and previously inaccessible cellular models of FRDA. These models enable studies of the molecular mechanisms underlying GAA-induced pathology, as well as providing an exciting tool for the screening and testing of novel disease-modifying therapies. This review explores how the use of iPSCs to study FRDA has developed over the past decade, as well as discussing the enormous therapeutic potentials of iPSC-derived models, their current limitations and their future direction within the field of FRDA research.
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Affiliation(s)
- Saumya Maheshwari
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Gabriela Vilema-Enríquez
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
| | - Richard Wade-Martins
- Department of Physiology, Anatomy and Genetics, Kavli Institute for Nanoscience Discovery, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
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10
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Angulo MB, Bertalovitz A, Argenziano MA, Yang J, Patel A, Zesiewicz T, McDonald TV. Frataxin deficiency alters gene expression in Friedreich ataxia derived IPSC-neurons and cardiomyocytes. Mol Genet Genomic Med 2022; 11:e2093. [PMID: 36369844 PMCID: PMC9834160 DOI: 10.1002/mgg3.2093] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 09/16/2022] [Accepted: 10/27/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Friedreich's ataxia (FRDA) is an autosomal recessive disease, whereby homozygous inheritance of an expanded GAA trinucleotide repeat expansion in the first intron of the FXN gene leads to transcriptional repression of the encoded protein frataxin. FRDA is a progressive neurodegenerative disorder, but the primary cause of death is heart disease which occurs in 60% of the patients. Several functions of frataxin have been proposed, but none of them fully explain why its deficiency causes the FRDA phenotypes nor why the most affected cell types are neurons and cardiomyocytes. METHODS To investigate, we generated iPSC-derived neurons (iNs) and cardiomyocytes (iCMs) from an FRDA patient and upregulated FXN expression via lentivirus without altering genomic GAA repeats at the FXN locus. RESULTS RNA-seq and differential gene expression enrichment analyses demonstrated that frataxin deficiency affected the expression of glycolytic pathway genes in neurons and extracellular matrix pathway genes in cardiomyocytes. Genes in these pathways were differentially expressed when compared to a control and restored to control levels when FRDA cells were supplemented with frataxin. CONCLUSIONS These results offer novel insight into specific roles of frataxin deficiency pathogenesis in neurons and cardiomyocytes.
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Affiliation(s)
- Mariana B. Angulo
- Heart Institute, Morsani College of Medicine, University of South FloridaTampaFloridaUSA,Department of Molecular Pharmacology & PhysiologyMorsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Alexander Bertalovitz
- Heart Institute, Morsani College of Medicine, University of South FloridaTampaFloridaUSA,Department of Medicine (Cardiology)Morsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Mariana A. Argenziano
- Heart Institute, Morsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Jiajia Yang
- Heart Institute, Morsani College of Medicine, University of South FloridaTampaFloridaUSA,Department of Molecular Pharmacology & PhysiologyMorsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Aarti Patel
- Department of Medicine (Cardiology)Morsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Theresa Zesiewicz
- Department of NeurologyMorsani College of Medicine, University of South FloridaTampaFloridaUSA
| | - Thomas V. McDonald
- Heart Institute, Morsani College of Medicine, University of South FloridaTampaFloridaUSA,Department of Molecular Pharmacology & PhysiologyMorsani College of Medicine, University of South FloridaTampaFloridaUSA,Department of Medicine (Cardiology)Morsani College of Medicine, University of South FloridaTampaFloridaUSA
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11
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Elumalai S, Karunakaran U, Moon JS, Won KC. Ferroptosis Signaling in Pancreatic β-Cells: Novel Insights & Therapeutic Targeting. Int J Mol Sci 2022; 23:13679. [PMID: 36430158 PMCID: PMC9690757 DOI: 10.3390/ijms232213679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/02/2022] [Accepted: 11/05/2022] [Indexed: 11/10/2022] Open
Abstract
Metabolic stress impairs pancreatic β-cell survival and function in diabetes. Although the pathophysiology of metabolic stress is complex, aberrant tissue damage and β-cell death are brought on by an imbalance in redox equilibrium due to insufficient levels of endogenous antioxidant expression in β-cells. The vulnerability of β-cells to oxidative damage caused by iron accumulation has been linked to contributory β-cell ferroptotic-like malfunction under diabetogenic settings. Here, we take into account recent findings on how iron metabolism contributes to the deregulation of the redox response in diabetic conditions as well as the ferroptotic-like malfunction in the pancreatic β-cells, which may offer insights for deciphering the pathomechanisms and formulating plans for the treatment or prevention of metabolic stress brought on by β-cell failure.
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Affiliation(s)
- Suma Elumalai
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
| | - Udayakumar Karunakaran
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
| | - Jun-Sung Moon
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea
| | - Kyu-Chang Won
- Innovative Center for Aging Research, Yeungnam University Medical Center, Daegu 42415, Korea
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu 42415, Korea
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12
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Vásquez-Trincado C, Dunn J, Han JI, Hymms B, Tamaroff J, Patel M, Nguyen S, Dedio A, Wade K, Enigwe C, Nichtova Z, Lynch DR, Csordas G, McCormack SE, Seifert EL. Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle. JCI Insight 2022; 7:e155201. [PMID: 35531957 PMCID: PMC9090249 DOI: 10.1172/jci.insight.155201] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/09/2022] [Indexed: 12/03/2022] Open
Abstract
Friedreich's ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, we show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, we used a transgenic mouse model of whole-body inducible and progressive FXN depletion. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.
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Affiliation(s)
- César Vásquez-Trincado
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Julia Dunn
- Division of Endocrinology and Diabetes and
| | - Ji In Han
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Briyanna Hymms
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | | | - Monika Patel
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | | | - Anna Dedio
- Division of Endocrinology and Diabetes and
| | | | | | - Zuzana Nichtova
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - David R. Lynch
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Neurology and
| | - Gyorgy Csordas
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Shana E. McCormack
- Division of Endocrinology and Diabetes and
- Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Erin L. Seifert
- Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College and
- MitoCare Center, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
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13
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Tamaroff J, DeDio A, Wade K, Wells M, Park C, Leavens K, Rummey C, Kelly A, Lynch DR, McCormack SE. Friedreich's Ataxia related Diabetes: Epidemiology and management practices. Diabetes Res Clin Pract 2022; 186:109828. [PMID: 35301072 PMCID: PMC9075677 DOI: 10.1016/j.diabres.2022.109828] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 03/04/2022] [Accepted: 03/09/2022] [Indexed: 01/21/2023]
Abstract
AIMS Friedreich's Ataxia (FRDA) is a progressive neuromuscular disorder typically caused by GAA triplet repeat expansions in both frataxin gene alleles. FRDA can be complicated by diabetes mellitus (DM). The objective of this study was to describe the prevalence of, risk factors for, and management practices of FRDA-related DM. METHODS FACOMS, a prospective, multi-site natural history study, includes 1,104 individuals. Extracted data included the presence of DM and other co-morbidities, genetic diagnosis, and markers of disease severity. We performed detailed medical record review and a survey for the subset of individuals with FRDA-related DM followed at one FACOMS site, Children's Hospital of Philadelphia. RESULTS FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common and newer glucose-lowering agents were used rarely. CONCLUSIONS Clinical factors identify individuals at increased risk for FRDA-related DM. Future studies should test strategies for FRDA-related DM screening and management, in particular the potential role for novel glucose-lowering therapies in preventing or delaying FRDA-related cardiac disease.
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Affiliation(s)
- Jaclyn Tamaroff
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
| | - Anna DeDio
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Kristin Wade
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - McKenzie Wells
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Courtney Park
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Karla Leavens
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | | | - Andrea Kelly
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Shana E McCormack
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
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14
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Rufini A, Malisan F, Condò I, Testi R. Drug Repositioning in Friedreich Ataxia. Front Neurosci 2022; 16:814445. [PMID: 35221903 PMCID: PMC8863941 DOI: 10.3389/fnins.2022.814445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.
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Affiliation(s)
- Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
- *Correspondence: Alessandra Rufini,
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
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15
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Shah S, Dooms MM, Amaral-Garcia S, Igoillo-Esteve M. Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders. Front Pharmacol 2022; 12:768023. [PMID: 34992533 PMCID: PMC8724568 DOI: 10.3389/fphar.2021.768023] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing–based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington’s disease, Friedreich’s ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.
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Affiliation(s)
- Sweta Shah
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
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16
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Patel M, McCormick A, Tamaroff J, Dunn J, Mitchell JA, Lin KY, Farmer J, Rummey C, Perlman SL, Delatycki MB, Wilmot GR, Mathews KD, Yoon G, Hoyle J, Corti M, Subramony S, Zesiewicz T, Lynch D, McCormack SE. Body Mass Index and Height in the Friedreich Ataxia Clinical Outcome Measures Study. Neurol Genet 2021; 7:e638. [PMID: 34786480 PMCID: PMC8589265 DOI: 10.1212/nxg.0000000000000638] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 08/31/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND OBJECTIVES Body mass index (BMI) and height are important indices of health. We tested the association between these outcomes and clinical characteristics in Friedreich ataxia (FRDA), a progressive neuromuscular disorder. METHODS Participants (N = 961) were enrolled in a prospective natural history study (Friedreich Ataxia Clinical Outcome Measure Study). Age- and sex-specific BMI and height Z-scores were calculated using CDC 2000 references for participants younger than 18 years. For adults aged 18 years or older, height Z-scores were also calculated, and absolute BMI was reported. Univariate and multivariate linear regression analyses tested the associations between exposures, covariates, and BMI or height measured at the baseline visit. In children, the superimposition by translation and rotation analysis method was used to compare linear growth trajectories between FRDA and a healthy reference cohort, the Bone Mineral Density in Childhood Study (n = 1,535 used for analysis). RESULTS Median age at the baseline was 20 years (IQR, 13-33 years); 49% (n = 475) were women. A substantial proportion of children (17%) were underweight (BMI-Z < fifth percentile), and female sex was associated with lower BMI-Z (β = -0.34, p < 0.05). In adults, older age was associated with higher BMI (β = 0.09, p < 0.05). Regarding height, in children, older age (β -0.06, p < 0.05) and worse modified Friedreich Ataxia Rating Scale (mFARS) scores (β = -1.05 for fourth quartile vs first quartile, p < 0.01) were associated with shorter stature. In girls, the magnitude of the pubertal growth spurt was less, and in boys, the pubertal growth spurt occurred later (p < 0.001 for both) than in a healthy reference cohort. In adults, in unadjusted analyses, both earlier age of FRDA symptom onset (=0.09, p < 0.05) and longer guanine-adenine-adenine repeat length (shorter of the 2 GAA repeats, β = -0.12, p < 0.01) were associated with shorter stature. Both adults and children with higher mFARS scores and/or who were nonambulatory were less likely to have height and weight measurements recorded at clinical visits. DISCUSSION FRDA affects both weight gain and linear growth. These insights will inform assessments of affected individuals in both research and clinical settings.
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Affiliation(s)
- Maya Patel
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Ashley McCormick
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Jaclyn Tamaroff
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Julia Dunn
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Jonathan A. Mitchell
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Kimberly Y. Lin
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Jennifer Farmer
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Christian Rummey
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Susan L. Perlman
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Martin B. Delatycki
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - George R. Wilmot
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Katherine D. Mathews
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Grace Yoon
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Joseph Hoyle
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Manuela Corti
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - S.H. Subramony
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Theresa Zesiewicz
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - David Lynch
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
| | - Shana E. McCormack
- From the Division of Neurology (M.P., A.M.C., J.F., D.L.), Children's Hospital of Philadelphia; Department of Neurology (M.P., A.M.C., D.L.), Perelman School of Medicine at the University of Pennsylvania; Division of Endocrinology and Diabetes (J.T., J.D., S.E.M.), Children's Hospital of Philadelphia; Department of Pediatrics (J.A.M, K.Y.L., S.E.M.), Perelman School of Medicine at the University of Pennsylvania; Division of Gastroenterology (J.A.M.), Hepatology and Nutrition, Children's Hospital of Philadelphia; Division of Cardiology (K.Y.L), Children's Hospital of Philadelphia; Friedreich's Ataxia Research Alliance (J.F.); Clinical Data Science GmbH (C.R.), Basel, Switzerland; Department of Neurology (S.L.P), University of California Los Angeles; Murdoch Children's Research Institute (M.B.D.), Victoria, Australia; Department of Neurology (G.R.W), Emory University School of Medicine, Atlanta, Georgia; Department of Pediatrics (K.D.M.), University of Iowa Carver College of Medicine, Iowa; Divisions of Neurology (G.Y.) and Clinical and Metabolic Genetics, Department of Paediatrics, the Hospital for Sick Children, University of Toronto, Ontario, Canada; Department of Neurology (J.H.), Ohio State University College of Medicine, Columbus, Ohio; Department of Neurology (M.C., S.H.S.), University of Florida, College of Medicine, Gainesville, Florida; Department of Neurology (T.Z.), University of South Florida, Tampa, Florida
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Cai Z, Liu F, Yang Y, Li D, Hu S, Song L, Yu S, Li T, Liu B, Luo H, Zhang W, Zhou Z, Zhang J. GRB10 regulates β cell mass by inhibiting β cell proliferation and stimulating β cell dedifferentiation. J Genet Genomics 2021; 49:208-216. [PMID: 34861413 DOI: 10.1016/j.jgg.2021.11.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 11/07/2021] [Accepted: 11/15/2021] [Indexed: 12/14/2022]
Abstract
Decreased functional β-cell mass is the hallmark of diabetes, but the cause of this metabolic defect remains elusive. Here, we show that the expression levels of the growth factor receptor-bound protein 10 (GRB10), a negative regulator of insulin and mTORC1 signaling, are markedly induced in islets of diabetic mice and high glucose-treated insulinoma cell line INS-1cells. β-cell-specific knockout of Grb10 in mice increased β-cell mass and improved β-cell function. Grb10-deficient β-cells exhibit enhanced mTORC1 signaling and reduced β-cell dedifferentiation, which could be blocked by rapamycin. On the contrary, Grb10 overexpression induced β-cell dedifferentiation in MIN6 cells. Our study identifies GRB10 as a critical regulator of β-cell dedifferentiation and β-cell mass, which exerts its effect by inhibiting mTORC1 signaling.
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Affiliation(s)
- Zixin Cai
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Fen Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yan Yang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Shanbiao Hu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Lei Song
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Shaojie Yu
- Department of Urological Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ting Li
- Department of Liver Organ Transplantation, the Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Bilian Liu
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Hairong Luo
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Weiping Zhang
- Department of Pathophysiology, Naval Medical University, Shanghai 200433, China
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China.
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18
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Villa C, Legato M, Umbach A, Riganti C, Jones R, Martini B, Boido M, Medana C, Facchinetti I, Barni D, Pinto M, Arguello T, Belicchi M, Fagiolari G, Liaci C, Moggio M, Ruffo R, Moraes CT, Monguzzi A, Merlo GR, Torrente Y. Treatment with ROS detoxifying gold quantum clusters alleviates the functional decline in a mouse model of Friedreich ataxia. Sci Transl Med 2021; 13:13/607/eabe1633. [PMID: 34408077 DOI: 10.1126/scitranslmed.abe1633] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 06/15/2021] [Indexed: 12/15/2022]
Abstract
Friedreich ataxia (FRDA) is caused by the reduced expression of the mitochondrial protein frataxin (FXN) due to an intronic GAA trinucleotide repeat expansion in the FXN gene. Although FRDA has no cure and few treatment options, there is research dedicated to finding an agent that can curb disease progression and address symptoms as neurobehavioral deficits, muscle endurance, and heart contractile dysfunctions. Because oxidative stress and mitochondrial dysfunctions are implicated in FRDA, we demonstrated the systemic delivery of catalysts activity of gold cluster superstructures (Au8-pXs) to improve cell response to mitochondrial reactive oxygen species and thereby alleviate FRDA-related pathology in mesenchymal stem cells from patients with FRDA. We also found that systemic injection of Au8-pXs ameliorated motor function and cardiac contractility of YG8sR mouse model that recapitulates the FRDA phenotype. These effects were associated to long-term improvement of mitochondrial functions and antioxidant cell responses. We related these events to an increased expression of frataxin, which was sustained by reduced autophagy. Overall, these results encourage further optimization of Au8-pXs in experimental clinical strategies for the treatment of FRDA.
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Affiliation(s)
- Chiara Villa
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Via F. Sforza 35, 20122 Milano, Italy
| | - Mariella Legato
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Via F. Sforza 35, 20122 Milano, Italy
| | - Alessandro Umbach
- Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza, 52 10126 Torino, Italy
| | - Chiara Riganti
- Department of Oncology, University of Turin, Via Santena 5/bis, 10126 Torino, Italy
| | - Rebecca Jones
- Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza, 52 10126 Torino, Italy
| | - Beatrice Martini
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Via F. Sforza 35, 20122 Milano, Italy
| | - Marina Boido
- Department of Neuroscience "Rita Levi Montalcini", Neuroscience Institute Cavalieri Ottolenghi, University of Turin, Regione Gonzole 10, Orbassano,10043 Torino, Italy
| | - Claudio Medana
- Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza, 52 10126 Torino, Italy
| | - Irene Facchinetti
- Department of Material Science, University of Milano Bicocca, Via R. Cozzi 55, 20125 Milano, Italy
| | - Dario Barni
- Department of Material Science, University of Milano Bicocca, Via R. Cozzi 55, 20125 Milano, Italy
| | - Milena Pinto
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Tania Arguello
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Marzia Belicchi
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Via F. Sforza 35, 20122 Milano, Italy
| | - Gigliola Fagiolari
- Neuromuscular and Rare Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy
| | - Carla Liaci
- Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza, 52 10126 Torino, Italy
| | - Maurizio Moggio
- Neuromuscular and Rare Diseases Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via F. Sforza 35, 20122 Milan, Italy
| | - Riccardo Ruffo
- Department of Material Science, University of Milano Bicocca, Via R. Cozzi 55, 20125 Milano, Italy
| | - Carlos T Moraes
- Department of Neurology, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Angelo Monguzzi
- Department of Material Science, University of Milano Bicocca, Via R. Cozzi 55, 20125 Milano, Italy
| | - Giorgio R Merlo
- Department of Molecular Biotechnology and Health Science, University of Turin, Via Nizza, 52 10126 Torino, Italy
| | - Yvan Torrente
- Stem Cell Laboratory, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Centro Dino Ferrari, Via F. Sforza 35, 20122 Milano, Italy.
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19
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Neuro-Ophthalmological Findings in Friedreich's Ataxia. J Pers Med 2021; 11:jpm11080708. [PMID: 34442352 PMCID: PMC8398238 DOI: 10.3390/jpm11080708] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 07/08/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022] Open
Abstract
Friedreich ataxia (FRDA) is a progressive neurodegenerative disease caused by a severe autosomal recessive genetic disorder of the central nervous (CNS) and peripheral nervous system (PNS), affecting children and young adults. Its onset is before 25 years of age, with mean ages of onset and death between 11 and 38 years, respectively. The incidence is 1 in 30,000–50,000 persons. It is caused, in 97% of cases, by a homozygous guanine-adenine-adenine (GAA) trinucleotide mutation in the first intron of the frataxin (FXN) gene on chromosome 9 (9q13–q1.1). The mutation of this gene causes a deficiency of frataxin, which induces an altered inflow of iron into the mitochondria, increasing the nervous system’s vulnerability to oxidative stress. The main clinical signs include spinocerebellar ataxia with sensory loss and disappearance of deep tendon reflexes, cerebellar dysarthria, cardiomyopathy, and scoliosis. Diabetes, hearing loss, and pes cavus may also occur, and although most patients with FRDA do not present with symptomatic visual impairment, 73% present with clinical neuro-ophthalmological alterations such as optic atrophy and altered eye movement, among others. This review provides a brief overview of the main aspects of FRDA and then focuses on the ocular involvement of this pathology and the possible use of retinal biomarkers.
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20
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Santos J, Woloski JR, Wu N. Polyuria and Acute Hyperglycemia Secondary to New-Onset Diabetes in a Young Woman With Friedreich's Ataxia. Cureus 2021; 13:e16032. [PMID: 34336519 PMCID: PMC8319161 DOI: 10.7759/cureus.16032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/29/2021] [Indexed: 11/05/2022] Open
Abstract
A 23-year-old woman with progressive Friedreich's ataxia (FRDA) presented to a local urgent care facility for urinary urgency and frequency. A urinalysis showed the presence of trace ketones and glucose, and point-of-care testing revealed severely elevated glucose. The patient was referred to the emergency department and was admitted for further evaluation of hyperglycemia. Laboratory tests were negative for a urinary tract infection; however, results revealed elevated serum glucose and hemoglobin A1C. She was diagnosed with new-onset diabetes mellitus and started on insulin therapy. Management of her diabetes was complicated due to advanced neurodegenerative symptoms related to FRDA. An individualized treatment plan and coordination of care with her home facility were essential for managing her diabetes.
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Affiliation(s)
- Jasmine Santos
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
| | - Jason R Woloski
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
| | - Natasha Wu
- Family Medicine, Geisinger Health System, Geisinger Commonwealth School of Medicine, Wilkes-Barre, USA
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21
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Lynch DR, Schadt K, Kichula E, McCormack S, Lin KY. Friedreich Ataxia: Multidisciplinary Clinical Care. J Multidiscip Healthc 2021; 14:1645-1658. [PMID: 34234452 PMCID: PMC8253929 DOI: 10.2147/jmdh.s292945] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 06/04/2021] [Indexed: 12/17/2022] Open
Abstract
Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000-100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.
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Affiliation(s)
- David R Lynch
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kim Schadt
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Elizabeth Kichula
- Division of Neurology, Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Shana McCormack
- Division of Endocrinology, Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
| | - Kimberly Y Lin
- Division of Cardiology, Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine, Philadelphia, PA, 19104, USA
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22
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Le Y, Zhang Z, Wang C, Lu D. Ferroptotic Cell Death: New Regulatory Mechanisms for Metabolic Diseases. Endocr Metab Immune Disord Drug Targets 2021; 21:785-800. [DOI: 10.2174/1871530320666200731175328] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/06/2020] [Accepted: 07/07/2020] [Indexed: 11/22/2022]
Abstract
Background:
Cell death is a fundamental biological phenomenon that contributes to the
pathogenesis of various diseases. Regulation of iron and iron metabolism has received considerable
research interests especially concerning the progression of metabolic diseases.
Discussion:
Emerging evidence shows that ferroptosis, a non-apoptotic programmed cell death induced by iron-dependent
lipid peroxidation, contributes to the development of complex diseases such as non-alcoholic steatohepatitis, cardiomyopathy, renal ischemia-reperfusion, and neurodegenerative diseases. Therefore, inhibiting ferroptosis can improve the pathophysiology of associated metabolic diseases. This review describes the vital role of ferroptosis in mediating the development
of certain metabolic diseases. Besides, the potential risk of iron and ferroptosis in atherosclerosis and cardiovascular diseases is also described. Iron overload and ferroptosis are potential secondary causes of death in metabolic diseases. Moreover,
this review also provides potential novel approaches against ferroptosis based on recent research advances.
Conclusion:
Several controversies exist concerning mechanisms underlying ferroptotic cell death in metabolic diseases, particularly in atherosclerosis. Since ferroptosis participates in the progression of metabolic diseases such as non-alcoholic steatohepatitis (NASH), there is a need to develop new drugs targeting ferroptosis to alleviate such diseases.
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Affiliation(s)
- Yifei Le
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zhijie Zhang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Cui Wang
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
| | - Dezhao Lu
- College of Life Science, Zhejiang Chinese Medical University, Hangzhou, China
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23
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Sanchez Caballero L, Gorgogietas V, Arroyo MN, Igoillo-Esteve M. Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:139-256. [PMID: 33832649 DOI: 10.1016/bs.ircmb.2021.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
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Affiliation(s)
- Laura Sanchez Caballero
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Vyron Gorgogietas
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Maria Nicol Arroyo
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/.
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24
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Hui CK, Dedkova EN, Montgomery C, Cortopassi G. Dimethyl fumarate dose-dependently increases mitochondrial gene expression and function in muscle and brain of Friedreich's ataxia model mice. Hum Mol Genet 2021; 29:3954-3965. [PMID: 33432356 DOI: 10.1093/hmg/ddaa282] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 12/16/2020] [Accepted: 12/23/2020] [Indexed: 01/03/2023] Open
Abstract
Previously we showed that dimethyl fumarate (DMF) dose-dependently increased mitochondrial gene expression and function in cells and might be considered as a therapeutic for inherited mitochondrial disease, including Friedreich's ataxia (FA). Here we tested DMF's ability to dose-dependently increase mitochondrial function, mitochondrial gene expression (frataxin and cytochrome oxidase protein) and mitochondrial copy number in C57BL6 wild-type mice and the FXNKD mouse model of FA. We first dosed DMF at 0-320 mg/kg in C57BL6 mice and observed significant toxicity above 160 mg/kg orally, defining the maximum tolerated dose. Oral dosing of C57BL6 mice in the range 0-160 mg/kg identified a maximum increase in aconitase activity and mitochondrial gene expression in brain and quadriceps at 110 mg/kg DMF, thus defining the maximum effective dose (MED). The MED of DMF in mice overlaps the currently approved human-equivalent doses of DMF prescribed for multiple sclerosis (480 mg/day) and psoriasis (720 mg/day). In the FXNKD mouse model of FA, which has a doxycycline-induced deficit of frataxin protein, we observed significant decreases of multiple mitochondrial parameters, including deficits in brain mitochondrial Complex 2, Complex 4 and aconitase activity, supporting the idea that frataxin deficiency reduces mitochondrial gene expression, mitochondrial functions and biogenesis. About 110 mg/kg of oral DMF rescued these enzyme activities in brain and rescued frataxin and cytochrome oxidase expression in brain, cerebellum and quadriceps muscle of the FXNKD mouse model. Taken together, these results support the idea of using fumarate-based molecules to treat FA or other mitochondrial diseases.
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Affiliation(s)
- Chun Kiu Hui
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Elena N Dedkova
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Claire Montgomery
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
| | - Gino Cortopassi
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA
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Abstract
Although type 1 diabetes mellitus and, to a lesser extent, type 2 diabetes mellitus, are the prevailing forms of diabetes in youth, atypical forms of diabetes are not uncommon and may require etiology-specific therapies. By some estimates, up to 6.5% of children with diabetes have monogenic forms. Mitochondrial diabetes and cystic fibrosis related diabetes are less common but often noted in the underlying disease. Atypical diabetes should be considered in patients with a known disorder associated with diabetes, aged less than 25 years with nonautoimmune diabetes and without typical characteristics of type 2 diabetes mellitus, and/or with comorbidities associated with atypical diabetes.
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Affiliation(s)
- Jaclyn Tamaroff
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA.
| | - Marissa Kilberg
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA
| | - Sara E Pinney
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA
| | - Shana McCormack
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA
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26
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Georgiadou E, Rutter GA. Control by Ca 2+ of mitochondrial structure and function in pancreatic β-cells. Cell Calcium 2020; 91:102282. [PMID: 32961506 PMCID: PMC7116533 DOI: 10.1016/j.ceca.2020.102282] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/25/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022]
Abstract
Mitochondria play a central role in glucose metabolism and the stimulation of insulin secretion from pancreatic β-cells. In this review, we discuss firstly the regulation and roles of mitochondrial Ca2+ transport in glucose-regulated insulin secretion, and the molecular machinery involved. Next, we discuss the evidence that mitochondrial dysfunction in β-cells is associated with type 2 diabetes, from a genetic, functional and structural point of view, and then the possibility that these changes may in part be mediated by dysregulation of cytosolic Ca2+. Finally, we review the importance of preserved mitochondrial structure and dynamics for mitochondrial gene expression and their possible relevance to the pathogenesis of type 2 diabetes.
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Affiliation(s)
- Eleni Georgiadou
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, du Cane Road, London, W12 0NN, UK
| | - Guy A Rutter
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, du Cane Road, London, W12 0NN, UK.
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27
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Rutter GA, Georgiadou E, Martinez-Sanchez A, Pullen TJ. Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity. Diabetologia 2020; 63:1990-1998. [PMID: 32894309 PMCID: PMC7476987 DOI: 10.1007/s00125-020-05205-5] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 05/05/2020] [Indexed: 12/24/2022]
Abstract
All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed ('disallowed') in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1-7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell-beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion. Graphical abstract.
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Affiliation(s)
- Guy A Rutter
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Republic of Singapore.
| | - Eleni Georgiadou
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Aida Martinez-Sanchez
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - Timothy J Pullen
- Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
- Department of Diabetes, School of Life Course Science, Faculty of Life Science and Medicine, King's College London, London, UK
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28
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Minsart C, Rorive S, Lemmers A, Quertinmont E, Gustot T. N-acetylcysteine and glycyrrhizin combination: Benefit outcome in a murine model of acetaminophen-induced liver failure. World J Hepatol 2020; 12:596-618. [PMID: 33033567 PMCID: PMC7522565 DOI: 10.4254/wjh.v12.i9.596] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 06/29/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Acetaminophen overdose is the most frequent cause of drug-induced liver failure in developed countries. Substantial progress has been made in understanding the mechanism of hepatocellular injury, but N-acetylcysteine remains the only effective treatment despite its short therapeutic window. Thus, other hepatoprotective drugs are needed for the delayed treatment of acetaminophen-induced hepatotoxicity. Our interest focused on glycyrrhizin for its role as an inhibitor of high mobility group box 1 (HMGB1) protein, a member of the family of damage-associated molecular pattern, known to play an important pathological role in various diseases.
AIM To investigate the efficacy of the N-acetylcysteine/glycyrrhizin combination compared to N-acetylcysteine alone in the prevention of liver toxicity.
METHODS Eight-week-old C57BL/6J wild-type female mice were used for all our experiments. Mice fasted for 15 h were treated with acetaminophen (500 mg/kg) or vehicle (phosphate-buffered saline) by intraperitoneal injection and separated into the following groups: Glycyrrhizin (200 mg/kg); N-acetylcysteine (150 mg/kg); and N-acetylcysteine/glycyrrhizin. In all groups, mice were sacrificed 12 h following acetaminophen administration. The assessment of hepatotoxicity was performed by measuring plasma levels of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. Hepatotoxicity was also evaluated by histological examination of hematoxylin and eosin-stained tissues sections. Survival rates were compared between various groups using Kaplan-Meier curves.
RESULTS Consistent with data published in the literature, we confirmed that intraperitoneal administration of acetaminophen (500 mg/kg) in mice induced severe liver injury as evidenced by increases in alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase but also by liver necrosis score. Glycyrrhizin administration was shown to reduce the release of HMGB1 and significantly decreased the severity of liver injury. Thus, the co-administration of glycyrrhizin and N-acetylcysteine was investigated. Administered concomitantly with acetaminophen, the combination significantly reduced the severity of liver injury. Delayed administration of the combination of drugs, 2 h or 6 h after acetaminophen, also induced a significant decrease in hepatocyte necrosis compared to mice treated with N-acetylcysteine alone. In addition, administration of N-acetylcysteine/glycyrrhizin combination was associated with an improved survival rate compared to mice treated with only N-acetylcysteine.
CONCLUSION We demonstrate that, compared to N-acetylcysteine alone, co-administration of glycyrrhizin decreases the liver necrosis score and improves survival in a murine model of acetaminophen-induced liver injury. Our study opens a potential new therapeutic pathway in the prevention of acetaminophen hepatotoxicity.
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Affiliation(s)
- Charlotte Minsart
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Sandrine Rorive
- Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- DIAPATH-Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Gosselies 6041, Belgium
| | - Arnaud Lemmers
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Department of Gastroenterology, Hepato Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Eric Quertinmont
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
| | - Thierry Gustot
- Laboratory of Experimental Gastroenterology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Department of Gastroenterology, Hepato Pancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels 1070, Belgium
- Inserm Unité 1149, Centre de Recherche sur l’inflammation, Paris 75006, France
- UMR S_1149, Université Paris Diderot, Paris 75006, France
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29
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Li XY, Leung PS. Erastin-induced ferroptosis is a regulator for the growth and function of human pancreatic islet-like cell clusters. CELL REGENERATION (LONDON, ENGLAND) 2020; 9:16. [PMID: 32893325 PMCID: PMC7475162 DOI: 10.1186/s13619-020-00055-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/22/2020] [Indexed: 01/01/2023]
Abstract
Ferroptosis is a newly identified and novel form of cell death, which is characterized by an iron- and reactive oxygen species (ROS)-dependent manner. Potential utility of ferroptotic cell death has been recently proposed for cancer treatment. Meanwhile, ROS generation and apoptosis are inherently consequent to cell apoptosis and dysfunction during islet cell preparation and transplantation. Whether ferroptosis induction is a regulator for cell viability and function in human pancreatic islet-cell clusters (ICCs) derived from pancreatic progenitor cells (PPCs) remains elusive. We thus sought to induce ferroptosis in our established cell culture system of human PPCs/ICCs, examine the effects of ferroptosis on ICCs, and explore the potential regulatory pathways involved. Our results showed that ICCs were prone to the use of ferroptosis-inducing and inhibiting agents under our culture conditions. Erastin, a ferroptosis inducer, was found to trigger ferroptosis in ICCs, without the apparent detection of other types of cell death involved, such as apoptosis and autophagy. In corroboration, the use of ferroptosis inhibitor, ferrostatin-1 (Fer-1), was found to enhance the cell viability of ICCs and prevent them from ferroptosis as well as improve its function. Mechanistically, the erastin-induced ferroptosis in ICCs was probably mediated via activation of JNK/P38/MAPK pathways and upregulation of NOX4 expression. Together, our findings may provide a scientific basis of ferroptosis inhibition as a potential for the amelioration of ICC survival and functionality during islet transplantation in diabetic patients.
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Affiliation(s)
- Xing Yu Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Po Sing Leung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
- Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
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30
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Sherzai M, Valle A, Perry N, Kalef-Ezra E, Al-Mahdawi S, Pook M, Anjomani Virmouni S. HMTase Inhibitors as a Potential Epigenetic-Based Therapeutic Approach for Friedreich's Ataxia. Front Genet 2020; 11:584. [PMID: 32582297 PMCID: PMC7291394 DOI: 10.3389/fgene.2020.00584] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Accepted: 05/14/2020] [Indexed: 12/17/2022] Open
Abstract
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disorder caused by a homozygous GAA repeat expansion mutation in intron 1 of the frataxin gene (FXN), which instigates reduced transcription. As a consequence, reduced levels of frataxin protein lead to mitochondrial iron accumulation, oxidative stress, and ultimately cell death; particularly in dorsal root ganglia (DRG) sensory neurons and the dentate nucleus of the cerebellum. In addition to neurological disability, FRDA is associated with cardiomyopathy, diabetes mellitus, and skeletal deformities. Currently there is no effective treatment for FRDA and patients die prematurely. Recent findings suggest that abnormal GAA expansion plays a role in histone modification, subjecting the FXN gene to heterochromatin silencing. Therefore, as an epigenetic-based therapy, we investigated the efficacy and tolerability of two histone methyltransferase (HMTase) inhibitor compounds, BIX0194 (G9a-inhibitor) and GSK126 (EZH2-inhibitor), to specifically target and reduce H3K9me2/3 and H3K27me3 levels, respectively, in FRDA fibroblasts. We show that a combination treatment of BIX0194 and GSK126, significantly increased FXN gene expression levels and reduced the repressive histone marks. However, no increase in frataxin protein levels was observed. Nevertheless, our results are still promising and may encourage to investigate HMTase inhibitors with other synergistic epigenetic-based therapies for further preliminary studies.
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Affiliation(s)
- Mursal Sherzai
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Adamo Valle
- Energy Metabolism and Nutrition, Research Institute of Health Sciences (IUNICS) and Health Research Institute of Balearic Islands (IdISBa), University of Balearic Islands, Palma de Mallorca, Spain.,Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Nicholas Perry
- Division of Cancer Biology, The Institute of Cancer Research, London, United Kingdom
| | - Ester Kalef-Ezra
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Sahar Al-Mahdawi
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Mark Pook
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
| | - Sara Anjomani Virmouni
- Ataxia Research Group, Division of Biosciences, Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, United Kingdom
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31
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Oshima M, Pechberty S, Bellini L, Göpel SO, Campana M, Rouch C, Dairou J, Cosentino C, Fantuzzi F, Toivonen S, Marchetti P, Magnan C, Cnop M, Le Stunff H, Scharfmann R. Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity. Diabetologia 2020; 63:395-409. [PMID: 31796987 PMCID: PMC6946759 DOI: 10.1007/s00125-019-05046-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/14/2019] [Indexed: 01/02/2023]
Abstract
AIMS/HYPOTHESIS During the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment. METHODS EndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity. RESULTS EndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion. CONCLUSIONS/INTERPRETATION The present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity. DATA AVAILABILITY Microarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.
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Affiliation(s)
- Masaya Oshima
- Université Paris Descartes, Institut Cochin, Inserm U1016, 123 bd du Port-Royal, 75014, Paris, France
| | - Séverine Pechberty
- Université Paris Descartes, Institut Cochin, Inserm U1016, 123 bd du Port-Royal, 75014, Paris, France
| | - Lara Bellini
- Unité Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France
| | - Sven O Göpel
- Bioscience Metabolism, Research and Early Development Cardiovascular Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Mélanie Campana
- Unité Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France
| | - Claude Rouch
- Unité Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France
| | - Julien Dairou
- Université Paris Descartes CNRS UMR 8601, Paris, France
| | - Cristina Cosentino
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Federica Fantuzzi
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Sanna Toivonen
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
| | - Piero Marchetti
- University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy
| | - Christophe Magnan
- Unité Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, ULB Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Hervé Le Stunff
- Unité Biologie Fonctionnelle et Adaptative, CNRS UMR 8251, Paris, France
- Université Paris-Sud, CNRS UMR 9197, Institut des Neurosciences Paris-Saclay (Neuro-PSI) - CNRS UMR 9197, Orsay, France
| | - Raphaël Scharfmann
- Université Paris Descartes, Institut Cochin, Inserm U1016, 123 bd du Port-Royal, 75014, Paris, France.
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32
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Igoillo-Esteve M, Oliveira AF, Cosentino C, Fantuzzi F, Demarez C, Toivonen S, Hu A, Chintawar S, Lopes M, Pachera N, Cai Y, Abdulkarim B, Rai M, Marselli L, Marchetti P, Tariq M, Jonas JC, Boscolo M, Pandolfo M, Eizirik DL, Cnop M. Exenatide induces frataxin expression and improves mitochondrial function in Friedreich ataxia. JCI Insight 2020; 5:134221. [PMID: 31877117 PMCID: PMC7098728 DOI: 10.1172/jci.insight.134221] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/18/2019] [Indexed: 12/26/2022] Open
Abstract
Friedreich ataxia is an autosomal recessive neurodegenerative disease associated with a high diabetes prevalence. No treatment is available to prevent or delay disease progression. Friedreich ataxia is caused by intronic GAA trinucleotide repeat expansions in the frataxin-encoding FXN gene that reduce frataxin expression, impair iron-sulfur cluster biogenesis, cause oxidative stress, and result in mitochondrial dysfunction and apoptosis. Here we examined the metabolic, neuroprotective, and frataxin-inducing effects of glucagon-like peptide-1 (GLP-1) analogs in in vivo and in vitro models and in patients with Friedreich ataxia. The GLP-1 analog exenatide improved glucose homeostasis of frataxin-deficient mice through enhanced insulin content and secretion in pancreatic β cells. Exenatide induced frataxin and iron-sulfur cluster-containing proteins in β cells and brain and was protective to sensory neurons in dorsal root ganglia. GLP-1 analogs also induced frataxin expression, reduced oxidative stress, and improved mitochondrial function in Friedreich ataxia patients' induced pluripotent stem cell-derived β cells and sensory neurons. The frataxin-inducing effect of exenatide was confirmed in a pilot trial in Friedreich ataxia patients, showing modest frataxin induction in platelets over a 5-week treatment course. Taken together, GLP-1 analogs improve mitochondrial function in frataxin-deficient cells and induce frataxin expression. Our findings identify incretin receptors as a therapeutic target in Friedreich ataxia.
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Affiliation(s)
| | | | | | - Federica Fantuzzi
- ULB Center for Diabetes Research and
- Endocrinology and Metabolism, Department of Medicine and Surgery, University of Parma, Parma, Italy
| | | | | | - Amélie Hu
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Satyan Chintawar
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | | | | | - Ying Cai
- ULB Center for Diabetes Research and
| | | | - Myriam Rai
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Mohammad Tariq
- Pole of Endocrinology, Diabetes and Nutrition, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Jean-Christophe Jonas
- Pole of Endocrinology, Diabetes and Nutrition, Institute of Experimental and Clinical Research, Université Catholique de Louvain, Brussels, Belgium
| | - Marina Boscolo
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Massimo Pandolfo
- Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium
| | - Décio L. Eizirik
- ULB Center for Diabetes Research and
- Indiana Biosciences Research Institute, Indianapolis, Indiana, USA
| | - Miriam Cnop
- ULB Center for Diabetes Research and
- Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles, Brussels, Belgium
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33
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Turchi R, Tortolici F, Guidobaldi G, Iacovelli F, Falconi M, Rufini S, Faraonio R, Casagrande V, Federici M, De Angelis L, Carotti S, Francesconi M, Zingariello M, Morini S, Bernardini R, Mattei M, La Rosa P, Piemonte F, Lettieri-Barbato D, Aquilano K. Frataxin deficiency induces lipid accumulation and affects thermogenesis in brown adipose tissue. Cell Death Dis 2020; 11:51. [PMID: 31974344 PMCID: PMC6978516 DOI: 10.1038/s41419-020-2253-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/18/2022]
Abstract
Decreased expression of mitochondrial frataxin (FXN) causes Friedreich's ataxia (FRDA), a neurodegenerative disease with type 2 diabetes (T2D) as severe comorbidity. Brown adipose tissue (BAT) is a mitochondria-enriched and anti-diabetic tissue that turns excess energy into heat to maintain metabolic homeostasis. Here we report that the FXN knock-in/knock-out (KIKO) mouse shows hyperlipidemia, reduced energy expenditure and insulin sensitivity, and elevated plasma leptin, recapitulating T2D-like signatures. FXN deficiency leads to disrupted mitochondrial ultrastructure and oxygen consumption as well as lipid accumulation in BAT. Transcriptomic data highlights cold intolerance in association with iron-mediated cell death (ferroptosis). Impaired PKA-mediated lipolysis and expression of genes controlling mitochondrial metabolism, lipid catabolism and adipogenesis were observed in BAT of KIKO mice as well as in FXN-deficient T37i brown and primary adipocytes. Significant susceptibility to ferroptosis was observed in adipocyte precursors that showed increased lipid peroxidation and decreased glutathione peroxidase 4. Collectively our data point to BAT dysfunction in FRDA and suggest BAT as promising therapeutic target to overcome T2D in FRDA.
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Affiliation(s)
- Riccardo Turchi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Flavia Tortolici
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Giulio Guidobaldi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Federico Iacovelli
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Mattia Falconi
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Stefano Rufini
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy
| | - Raffaella Faraonio
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Naples, Italy
| | - Viviana Casagrande
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Massimo Federici
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Lorenzo De Angelis
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Simone Carotti
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Maria Francesconi
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Maria Zingariello
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Sergio Morini
- Unit of Microscopic and Ultrastructural Anatomy, University Campus Bio-Medico, Rome, Italy
| | - Roberta Bernardini
- Interdepartmental Service Center-Station for Animal Technology (STA), University of Rome Tor Vergata, Rome, Italy
| | - Maurizio Mattei
- Interdepartmental Service Center-Station for Animal Technology (STA), University of Rome Tor Vergata, Rome, Italy
| | - Piergiorgio La Rosa
- Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Fiorella Piemonte
- Unit of Neuromuscular and Neurodegenerative Diseases, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Daniele Lettieri-Barbato
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.
- IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.
| | - Katia Aquilano
- Department Biology, University of Rome Tor Vergata, via della Ricerca Scientifica, Rome, Italy.
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34
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Tatsch E, De Carvalho JAM, Bollick YS, Duarte T, Duarte MMMF, Vaucher RA, Premaor MO, Comim FV, Moresco RN. Low frataxin mRNA expression is associated with inflammation and oxidative stress in patients with type 2 diabetes. Diabetes Metab Res Rev 2020; 36:e3208. [PMID: 31343823 DOI: 10.1002/dmrr.3208] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Revised: 06/04/2019] [Accepted: 07/16/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND The mitochondrial protein frataxin is involved in iron metabolism, as well as regulation of oxidative stress. To elucidate the association of frataxin with the pathophysiology of diabetes, we evaluated the mRNA levels of frataxin in leukocytes of patients with type 2 diabetes (T2D). In addition, we investigated the relation between frataxin mRNA levels, inflammatory cytokines, and oxidative stress biomarkers. METHODS A study including 150 subjects (115 patients with T2D and 35 healthy subjects) was performed to evaluate the frataxin mRNA levels in leukocytes. We assessed the relation between frataxin and interleukin (IL)-6, IL-1, tumour necrosis factor-alpha (TNF-α), total oxidation status (TOS), total antioxidant capacity (TAC), and serum iron. RESULTS The frataxin mRNA levels in the T2D group were significantly lower than those in healthy subjects. It was also demonstrated that T2D patients with frataxin mRNA levels in the lowest quartile had significantly elevated levels of serum iron, TOS, and inflammatory cytokines, such as TNF-α, IL-1, and IL-6, while TAC levels were significantly lower in this quartile when compared with the upper quartile. CONCLUSIONS Our findings showed that T2D patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.
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Affiliation(s)
- Etiane Tatsch
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - José A M De Carvalho
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
- Laboratory of Clinical Analysis, University Hospital, Santa Maria, RS, Brazil
| | - Yãnaí S Bollick
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Thiago Duarte
- Laboratory of Biogenomic, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Marta M M F Duarte
- Department of Health Sciences, Lutheran University of Brazil, Santa Maria, RS, Brazil
| | - Rodrigo A Vaucher
- Center of Chemical, Pharmaceutical and Food Sciences, Federal University of Pelotas, Pelotas, RS, Brazil
| | - Melissa O Premaor
- Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Fabio V Comim
- Department of Clinical Medicine, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Rafael N Moresco
- Laboratory of Clinical Biochemistry, Department of Clinical and Toxicological Analysis, Federal University of Santa Maria, Santa Maria, RS, Brazil
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35
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Garg M, Kulkarni SD, Shah KN, Hegde AU. Diabetes Mellitus as the Presenting Feature of Friedreich's Ataxia. J Neurosci Rural Pract 2019; 8:S117-S119. [PMID: 28936086 PMCID: PMC5602235 DOI: 10.4103/jnrp.jnrp_112_17] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Patients with Friedreich's ataxia (FA) are at an increased risk of developing diabetes mellitus and glucose intolerance. Diabetes usually develops many years after the initial presentation. We report an 8-year-old girl who initially presented with diabetic ketoacidosis and was treated as a case of insulin-dependent diabetes mellitus. Around a year later, she developed gait problems and ataxia. Cardiac involvement was detected on echocardiography. Genetic testing confirmed the diagnosis of FA. FA should be a diagnostic consideration in children presenting with diabetes and neurological issues, even with early presentation of the former. Early occurrence of diabetes and rapid progression of ataxia in this patient needs a better understanding of underlying genetic mechanisms.
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Affiliation(s)
- Meenal Garg
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Shilpa D Kulkarni
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Krishnakumar N Shah
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
| | - Anaita Udwadia Hegde
- Department of Pediatric Neurosciences, Bai Jerbai Wadia Hospital for Children, Mumbai, Maharashtra, India
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36
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Clay A, Hearle P, Schadt K, Lynch DR. New developments in pharmacotherapy for Friedreich ataxia. Expert Opin Pharmacother 2019; 20:1855-1867. [PMID: 31311349 DOI: 10.1080/14656566.2019.1639671] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Introduction: Friedreich ataxia (FRDA), a rare disease caused by the deficiency of the mitochondrial matrix protein frataxin, affects roughly 1 in 50,000 individuals worldwide. Current and emerging therapies focus on reversing the deleterious effects of such deficiency including mitochondrial augmentation and increasing frataxin levels, providing the possibility of treatment options for this physiologically complex, multisystem disorder. Areas covered: In this review article, the authors discuss the current and prior in vivo and in vitro research studies related to the treatment of FRDA, with a particular interest in future implications of each therapy. Expert opinion: Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.
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Affiliation(s)
- Alexandra Clay
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Patrick Hearle
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - Kim Schadt
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
| | - David R Lynch
- Division of Neurology, Children's Hospital of Philadelphia , Philadelphia , PA , USA
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37
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Lai JI, Nachun D, Petrosyan L, Throesch B, Campau E, Gao F, Baldwin KK, Coppola G, Gottesfeld JM, Soragni E. Transcriptional profiling of isogenic Friedreich ataxia neurons and effect of an HDAC inhibitor on disease signatures. J Biol Chem 2019; 294:1846-1859. [PMID: 30552117 PMCID: PMC6369281 DOI: 10.1074/jbc.ra118.006515] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/12/2018] [Indexed: 12/16/2022] Open
Abstract
Friedreich ataxia (FRDA) is a neurodegenerative disorder caused by transcriptional silencing of the frataxin (FXN) gene, resulting in loss of the essential mitochondrial protein frataxin. Based on the knowledge that a GAA·TTC repeat expansion in the first intron of FXN induces heterochromatin, we previously showed that 2-aminobenzamide-type histone deacetylase inhibitors (HDACi) increase FXN mRNA levels in induced pluripotent stem cell (iPSC)-derived FRDA neurons and in circulating lymphocytes from patients after HDACi oral administration. How the reduced expression of frataxin leads to neurological and other systemic symptoms in FRDA patients remains unclear. Similar to other triplet-repeat disorders, it is unknown why FRDA affects only specific cell types, primarily the large sensory neurons of the dorsal root ganglia and cardiomyocytes. The combination of iPSC technology and genome-editing techniques offers the unique possibility to address these questions in a relevant cell model of FRDA, obviating confounding effects of variable genetic backgrounds. Here, using "scarless" gene-editing methods, we created isogenic iPSC lines that differ only in the length of the GAA·TTC repeats. To uncover the gene expression signatures due to the GAA·TTC repeat expansion in FRDA neuronal cells and the effect of HDACi on these changes, we performed RNA-seq-based transcriptomic analysis of iPSC-derived central nervous system (CNS) and isogenic sensory neurons. We found that cellular pathways related to neuronal function, regulation of transcription, extracellular matrix organization, and apoptosis are affected by frataxin loss in neurons of the CNS and peripheral nervous system and that these changes are partially restored by HDACi treatment.
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Affiliation(s)
- Jiun-I Lai
- From the Departments of Molecular Medicine and
| | - Daniel Nachun
- the Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095
| | | | - Benjamin Throesch
- Neuroscience, The Scripps Research Institute, La Jolla, California 92037 and
| | | | - Fuying Gao
- the Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095
| | - Kristin K Baldwin
- Neuroscience, The Scripps Research Institute, La Jolla, California 92037 and
| | - Giovanni Coppola
- the Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, California 90095
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38
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Abstract
Friedreich's ataxia (FRDA) is a degenerative disease that affects both the central and the peripheral nervous systems and non-neural tissues including, mainly, heart, and endocrine pancreas. It is an autosomal recessive disease caused by a GAA triplet-repeat localized within an Alu sequence element in intron 1 of frataxin (FXN) gene, which encodes a mitochondrial protein FXN. This protein is essential for mitochondrial function by the involvement of iron-sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. Though iron toxicity is commonly thought to be mediated via Fenton reaction, oxidative stress seems not to be the main problem to result in detrimental effects on cell survival, particularly neuron survival. Therefore, the basic research on FXN function is urgently demanded to understand the disease. This chapter focuses on the outcome of FXN expression, regulation, and function in cellular or animal models of FRDA and on iron pathophysiology in the affected tissues. Finally, therapeutic strategies based on the control of iron toxicity and iron cellular redistribution are considered. The combination of multiple therapeutic targets including iron, oxidative stress, mitochondrial function, and FXN regulation is also proposed.
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Affiliation(s)
- Kuanyu Li
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, People's Republic of China.
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39
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Azzi AS, Cosentino C, Kibanda J, Féry F, Cnop M. OGTT is recommended for glucose homeostasis assessments in Friedreich ataxia. Ann Clin Transl Neurol 2018; 6:161-166. [PMID: 30656194 PMCID: PMC6331656 DOI: 10.1002/acn3.686] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 09/23/2018] [Accepted: 10/16/2018] [Indexed: 11/30/2022] Open
Abstract
Diabetes is a common complication of Friedreich ataxia, requiring sensitive diagnostic methods. Here, we compared the performance of different tests that assess glucose tolerance, insulin sensitivity, and β‐cell function in Friedreich ataxia patients, heterozygous FXN mutation carriers and controls. We find that diabetes is underdiagnosed with fasting glucose alone. The oral glucose tolerance test (OGTT) provides 1.2‐ to 3.5‐fold more diagnoses of impaired glucose homeostasis and diabetes, and adequately measures insulin sensitivity, insulin secretion, and β‐cell function. Clinicians in charge of Friedreich ataxia patients and researchers should incorporate the OGTT as an accurate diagnostic and research tool.
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Affiliation(s)
- Anne-Sophie Azzi
- Division of Endocrinology Erasmus Hospital Université Libre de Bruxelles Brussels Belgium
| | - Cristina Cosentino
- ULB Center for Diabetes Research Université Libre de Bruxelles Brussels Belgium
| | - Jésabelle Kibanda
- ULB Center for Diabetes Research Université Libre de Bruxelles Brussels Belgium
| | - Françoise Féry
- Division of Endocrinology Erasmus Hospital Université Libre de Bruxelles Brussels Belgium
| | - Miriam Cnop
- Division of Endocrinology Erasmus Hospital Université Libre de Bruxelles Brussels Belgium.,ULB Center for Diabetes Research Université Libre de Bruxelles Brussels Belgium
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40
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Chase JG, Desaive T, Bohe J, Cnop M, De Block C, Gunst J, Hovorka R, Kalfon P, Krinsley J, Renard E, Preiser JC. Improving glycemic control in critically ill patients: personalized care to mimic the endocrine pancreas. CRITICAL CARE : THE OFFICIAL JOURNAL OF THE CRITICAL CARE FORUM 2018; 22:182. [PMID: 30071851 PMCID: PMC6091026 DOI: 10.1186/s13054-018-2110-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 06/29/2018] [Indexed: 02/06/2023]
Abstract
There is considerable physiological and clinical evidence of harm and increased risk of death associated with dysglycemia in critical care. However, glycemic control (GC) currently leads to increased hypoglycemia, independently associated with a greater risk of death. Indeed, recent evidence suggests GC is difficult to safely and effectively achieve for all patients. In this review, leading experts in the field discuss this evidence and relevant data in diabetology, including the artificial pancreas, and suggest how safe, effective GC can be achieved in critically ill patients in ways seeking to mimic normal islet cell function. The review is structured around the specific clinical hurdles of: understanding the patient’s metabolic state; designing GC to fit clinical practice, safety, efficacy, and workload; and the need for standardized metrics. These aspects are addressed by reviewing relevant recent advances in science and technology. Finally, we provide a set of concise recommendations to advance the safety, quality, consistency, and clinical uptake of GC in critical care. This review thus presents a roadmap toward better, more personalized metabolic care and improved patient outcomes.
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Affiliation(s)
- J Geoffrey Chase
- Department of Mechanical Engineering, Centre for Bio-Engineering, University of Canterbury, Christchurch, New Zealand
| | - Thomas Desaive
- GIGA In-Silico Medicine, University of Liège, Liège, Belgium
| | - Julien Bohe
- Medical Intensive Care Unit, Lyon-Sud University Hospital, Pierre-Bénite, France
| | - Miriam Cnop
- ULB Center for Diabetes Research, and Division of Endocrinology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
| | - Christophe De Block
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, Edegem, Belgium
| | - Jan Gunst
- Clinical Division and Laboratory of Intensive Care Medicine, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Roman Hovorka
- University of Cambridge Metabolic Research Laboratories, Level 4, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK
| | - Pierre Kalfon
- Service de Réanimation polyvalente, Hôpital Louis Pasteur, CH de Chartres, Chartres, France
| | - James Krinsley
- Division of Critical Care, Department of Medicine, Stamford Hospital, Columbia University College of Physicians and Surgeons, Stamford, CT, USA
| | - Eric Renard
- Department of Endocrinology, Diabetes, Nutrition, and Institute of Functional Genomics, CNRS, INSERM, Montpellier University Hospital, University of Montpellier, Montpellier, France
| | - Jean-Charles Preiser
- Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070, Brussels, Belgium.
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Monnier V, Llorens JV, Navarro JA. Impact of Drosophila Models in the Study and Treatment of Friedreich's Ataxia. Int J Mol Sci 2018; 19:E1989. [PMID: 29986523 PMCID: PMC6073496 DOI: 10.3390/ijms19071989] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 06/26/2018] [Accepted: 07/03/2018] [Indexed: 02/07/2023] Open
Abstract
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therapeutic interventions. In this review, we aim to summarize the collection of findings provided by the Drosophila models but also to go one step beyond and propose the implications of these discoveries for the study and cure of this disorder. We will present the physiological, cellular and molecular phenotypes described in the fly, highlighting those that have given insight into the pathology and we will show how the ability of Drosophila to perform genetic and pharmacological screens has provided valuable information that is not easily within reach of other cellular or mammalian models.
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Affiliation(s)
- Véronique Monnier
- Unité de Biologie Fonctionnelle et Adaptative (BFA), Sorbonne Paris Cité, Université Paris Diderot, UMR8251 CNRS, 75013 Paris, France.
| | - Jose Vicente Llorens
- Department of Genetics, University of Valencia, Campus of Burjassot, 96100 Valencia, Spain.
| | - Juan Antonio Navarro
- Lehrstuhl für Entwicklungsbiologie, Universität Regensburg, 93040 Regensburg, Germany.
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Pappa A, Häusler MG, Veigel A, Tzamouranis K, Pfeifer MW, Schmidt A, Bökamp M, Haberland H, Wagner S, Brückel J, de Sousa G, Hackl L, Bollow E, Holl RW. Diabetes mellitus in Friedreich Ataxia: A case series of 19 patients from the German-Austrian diabetes mellitus registry. Diabetes Res Clin Pract 2018; 141:229-236. [PMID: 29763710 DOI: 10.1016/j.diabres.2018.05.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Revised: 04/22/2018] [Accepted: 05/08/2018] [Indexed: 10/16/2022]
Abstract
Friedreich ataxia (FRDA) is a multisystem autosomal recessive disease with progressive clinical course involving the neuromuscular and endocrine system. Diabetes mellitus (DM) is one typical non-neurological manifestation, caused by beta cell failure and insulin resistance. Because of its rarity, knowledge on DM in FRDA is limited. Based on data from 200,301 patients with DM of the German-Austrian diabetes registry (DPV) and two exemplary patient reports, characteristics of patients with DM and FRDA are compared with classical type 1 or type 2 diabetes. Diabetes phenotype in FRDA is intermediate between type 1 and type 2 diabetes with ketoacidosis being frequent at presentation and blood glucose levels similar to T1Dm but higher than in T2Dm (356 ± 165 and 384 ± 203 mg/dl). 63.2% of FRDA patients received insulin monotherapy, 21% insulin plus oral antidiabetics and 15.8% lifestyle change only, applying similar doses of insulin in all three groups. FRDA patients did not show overweight and HbA1c levels were even lower than in T1Dm or T2Dm patients, respectively, indicating good overall diabetes control. FRDADm can be controlled by individualized treatment regimen with insulin or oral antidiabetics. Patients with DM in FRDA may show a relevant risk to ketoacidotic complications, which should be avoided.
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Affiliation(s)
- Angeliki Pappa
- Dept. of Pediatrics, University Hospital RWTH Aachen, Aachen, Germany.
| | - Martin G Häusler
- Dept. of Pediatrics, Division of Neuropediatrics and Social Pediatrics, University Hospital RWTH Aachen, Germany
| | - Andreas Veigel
- Childrens Hospital Städtisches Klinikum Karlsruhe, Germany
| | | | | | - Andreas Schmidt
- Diabeteszentrum Dept. of Pediatrics, Christophorus-Kliniken Coesfeld, Germany
| | - Martin Bökamp
- Dpt. of Internal Medicine, Christophorus Kliniken Coesfeld/Duelmen, Germany
| | - Holger Haberland
- DiabetesZentrum für Kinder und Jugendliche Sana Kliniken Berlin-Brandenburg, Germany
| | | | | | | | - Lukas Hackl
- Dept. of Pediatrics, Medical University Innsbruck, Austria
| | - Esther Bollow
- Institute for Epidemiology and medical Biometry, ZIBMT, University of Ulm, Germany; German Center for Diabetes-Research (DZD), Munich-Neuherberg, Germany
| | - Reinhard W Holl
- Institute for Epidemiology and medical Biometry, ZIBMT, University of Ulm, Germany; German Center for Diabetes-Research (DZD), Munich-Neuherberg, Germany
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Edenharter O, Schneuwly S, Navarro JA. Mitofusin-Dependent ER Stress Triggers Glial Dysfunction and Nervous System Degeneration in a Drosophila Model of Friedreich's Ataxia. Front Mol Neurosci 2018; 11:38. [PMID: 29563863 PMCID: PMC5845754 DOI: 10.3389/fnmol.2018.00038] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 01/29/2018] [Indexed: 11/13/2022] Open
Abstract
Friedreich's ataxia (FRDA) is the most important recessive ataxia in the Caucasian population. It is caused by a deficit of the mitochondrial protein frataxin. Despite its pivotal effect on biosynthesis of iron-sulfur clusters and mitochondrial energy production, little is known about the influence of frataxin depletion on homeostasis of the cellular mitochondrial network. We have carried out a forward genetic screen to analyze genetic interactions between genes controlling mitochondrial homeostasis and Drosophila frataxin. Our screen has identified silencing of Drosophila mitofusin (Marf) as a suppressor of FRDA phenotypes in glia. Drosophila Marf is known to play crucial roles in mitochondrial fusion, mitochondrial degradation and in the interface between mitochondria and endoplasmic reticulum (ER). Thus, we have analyzed the effects of frataxin knockdown on mitochondrial morphology, mitophagy and ER function in our fly FRDA model using different histological and molecular markers such as tetramethylrhodamine, ethyl ester (TMRE), mitochondria-targeted GFP (mitoGFP), p62, ATG8a, LAMP1, Xbp1 and BiP/GRP78. Furthermore, we have generated the first Drosophila transgenic line containing the mtRosella construct under the UAS control to study the progression of the mitophagy process in vivo. Our results indicated that frataxin-deficiency had a small impact on mitochondrial morphology but enhanced mitochondrial clearance and altered the ER stress response in Drosophila. Remarkably, we demonstrate that downregulation of Marf suppresses ER stress in frataxin-deficient cells and this is sufficient to improve locomotor dysfunction, brain degeneration and lipid dyshomeostasis in our FRDA model. In agreement, chemical reduction of ER stress by means of two different compounds was sufficient to ameliorate the effects of frataxin deficiency in three different fly FRDA models. Altogether, our results strongly suggest that the protection mediated by Marf knockdown in glia is mainly linked to its role in the mitochondrial-ER tethering and not to mitochondrial dynamics or mitochondrial degradation and that ER stress is a novel and pivotal player in the progression and etiology of FRDA. This work might define a new pathological mechanism in FRDA, linking mitochondrial dysfunction due to frataxin deficiency and mitofusin-mediated ER stress, which might be responsible for characteristic cellular features of the disease and also suggests ER stress as a therapeutic target.
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Affiliation(s)
- Oliver Edenharter
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - Stephan Schneuwly
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
| | - Juan A. Navarro
- Department of Developmental Biology, Institute of Zoology, University of Regensburg, Regensburg, Germany
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Fex M, Nicholas LM, Vishnu N, Medina A, Sharoyko VV, Nicholls DG, Spégel P, Mulder H. The pathogenetic role of β-cell mitochondria in type 2 diabetes. J Endocrinol 2018; 236:R145-R159. [PMID: 29431147 DOI: 10.1530/joe-17-0367] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/15/2018] [Indexed: 12/17/2022]
Abstract
Mitochondrial metabolism is a major determinant of insulin secretion from pancreatic β-cells. Type 2 diabetes evolves when β-cells fail to release appropriate amounts of insulin in response to glucose. This results in hyperglycemia and metabolic dysregulation. Evidence has recently been mounting that mitochondrial dysfunction plays an important role in these processes. Monogenic dysfunction of mitochondria is a rare condition but causes a type 2 diabetes-like syndrome owing to β-cell failure. Here, we describe novel advances in research on mitochondrial dysfunction in the β-cell in type 2 diabetes, with a focus on human studies. Relevant studies in animal and cell models of the disease are described. Transcriptional and translational regulation in mitochondria are particularly emphasized. The role of metabolic enzymes and pathways and their impact on β-cell function in type 2 diabetes pathophysiology are discussed. The role of genetic variation in mitochondrial function leading to type 2 diabetes is highlighted. We argue that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
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Affiliation(s)
- Malin Fex
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Lisa M Nicholas
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Neelanjan Vishnu
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Anya Medina
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Vladimir V Sharoyko
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - David G Nicholls
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Peter Spégel
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
- Department of ChemistryCenter for Analysis and Synthesis, Lund University, Sweden
| | - Hindrik Mulder
- Department of Clinical Sciences in MalmöUnit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
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McCormick A, Farmer J, Perlman S, Delatycki M, Wilmot G, Matthews K, Yoon G, Hoyle C, Subramony SH, Zesiewicz T, Lynch DR, McCormack SE. Impact of diabetes in the Friedreich ataxia clinical outcome measures study. Ann Clin Transl Neurol 2017; 4:622-631. [PMID: 28904984 PMCID: PMC5590524 DOI: 10.1002/acn3.439] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 06/12/2017] [Accepted: 06/19/2017] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes. RESEARCH DESIGN AND METHODS Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes. RESULTS Mean age of participants was 30.1 years (SD 15.3, range: 7-82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA-associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: -0.56-0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals. CONCLUSIONS DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.
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Affiliation(s)
- Ashley McCormick
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
| | - Jennifer Farmer
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
- Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
| | - Susan Perlman
- Department of NeurologyUniversity of California Los AngelesLos AngelesCalifornia90095
| | - Martin Delatycki
- Department of GeneticsMurdoch Children's Research InstituteVictoriaAustralia
| | - George Wilmot
- Department of NeurologyEmory University School of MedicineAtlantaGeorgia30322
| | - Katherine Matthews
- Department of NeurologyUniversity of Iowa Carver College of MedicineIowa CityIowa52242
| | - Grace Yoon
- Clinical and Metabolic GeneticsHospital for Sick ChildrenTorontoCanada
| | - Chad Hoyle
- Department of NeurologyOhio State University College of MedicineColumbusOhio43210
| | - Sub H. Subramony
- Department of NeurologyUniversity of FloridaCollege of MedicineGainesvilleFlorida32610
| | | | - David R. Lynch
- Division of NeurologyChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
- Department of NeurologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
| | - Shana E. McCormack
- Department of PediatricsPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPennsylvania19104
- Division of Endocrinology and DiabetesChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvania19104
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Abdulkarim B, Hernangomez M, Igoillo-Esteve M, Cunha DA, Marselli L, Marchetti P, Ladriere L, Cnop M. Guanabenz Sensitizes Pancreatic β Cells to Lipotoxic Endoplasmic Reticulum Stress and Apoptosis. Endocrinology 2017; 158:1659-1670. [PMID: 28323924 DOI: 10.1210/en.2016-1773] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 02/24/2017] [Indexed: 12/18/2022]
Abstract
Deficient as well as excessive/prolonged endoplasmic reticulum (ER) stress signaling can lead to pancreatic β cell failure and the development of diabetes. Saturated free fatty acids (FFAs) such as palmitate induce lipotoxic ER stress in pancreatic β cells. One of the main ER stress response pathways is under the control of the protein kinase R-like endoplasmic reticulum kinase (PERK), leading to phosphorylation of the eukaryotic translation initiation factor 2 (eIF2α). The antihypertensive drug guanabenz has been shown to inhibit eIF2α dephosphorylation and protect cells from ER stress. Here we examined whether guanabenz protects pancreatic β cells from lipotoxicity. Guanabenz induced β cell dysfunction in vitro and in vivo in rodents and led to impaired glucose tolerance. The drug significantly potentiated FFA-induced cell death in clonal rat β cells and in rat and human islets. Guanabenz enhanced FFA-induced eIF2α phosphorylation and expression of the downstream proapoptotic gene C/EBP homologous protein (CHOP), which mediated the sensitization to lipotoxicity. Thus, guanabenz does not protect β cells from ER stress; instead, it potentiates lipotoxic ER stress through PERK/eIF2α/CHOP signaling. These data demonstrate the crucial importance of the tight regulation of eIF2α phosphorylation for the normal function and survival of pancreatic β cells.
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Affiliation(s)
- Baroj Abdulkarim
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Miriam Hernangomez
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | | | - Daniel A Cunha
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Lorella Marselli
- Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy
| | - Piero Marchetti
- Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy
| | - Laurence Ladriere
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Université Libre de Bruxelles, 1070 Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, 1070 Brussels, Belgium
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Bürk K. Friedreich Ataxia: current status and future prospects. CEREBELLUM & ATAXIAS 2017; 4:4. [PMID: 28405347 PMCID: PMC5383992 DOI: 10.1186/s40673-017-0062-x] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 03/24/2017] [Indexed: 01/23/2023]
Abstract
Friedreich ataxia (FA) represents the most frequent type of inherited ataxia. Most patients carry homozygous GAA expansions in the first intron of the frataxin gene on chromosome 9. Due to epigenetic alterations, frataxin expression is significantly reduced. Frataxin is a mitochondrial protein. Its deficiency leads to mitochondrial iron overload, defective energy supply and generation of reactive oxygen species. This review gives an overview over clinical and genetic aspects of FA and discusses current concepts of frataxin biogenesis and function as well as new therapeutic strategies.
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Affiliation(s)
- Katrin Bürk
- University of Marburg, and Paracelsus-Elena Klinik, Klinikstr. 16, 34128 Kassel, Germany
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48
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Gerber PA, Rutter GA. The Role of Oxidative Stress and Hypoxia in Pancreatic Beta-Cell Dysfunction in Diabetes Mellitus. Antioxid Redox Signal 2017; 26:501-518. [PMID: 27225690 PMCID: PMC5372767 DOI: 10.1089/ars.2016.6755] [Citation(s) in RCA: 437] [Impact Index Per Article: 54.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 05/25/2016] [Indexed: 12/16/2022]
Abstract
SIGNIFICANCE Metabolic syndrome is a frequent precursor of type 2 diabetes mellitus (T2D), a disease that currently affects ∼8% of the adult population worldwide. Pancreatic beta-cell dysfunction and loss are central to the disease process, although understanding of the underlying molecular mechanisms is still fragmentary. Recent Advances: Oversupply of nutrients, including glucose and fatty acids, and the subsequent overstimulation of beta cells, are believed to be an important contributor to insulin secretory failure in T2D. Hypoxia has also recently been implicated in beta-cell damage. Accumulating evidence points to a role for oxidative stress in both processes. Although the production of reactive oxygen species (ROS) results from enhanced mitochondrial respiration during stimulation with glucose and other fuels, the expression of antioxidant defense genes is unusually low (or disallowed) in beta cells. CRITICAL ISSUES Not all subjects with metabolic syndrome and hyperglycemia go on to develop full-blown diabetes, implying an important role in disease risk for gene-environment interactions. Possession of common risk alleles at the SLC30A8 locus, encoding the beta-cell granule zinc transporter ZnT8, may affect cytosolic Zn2+ concentrations and thus susceptibility to hypoxia and oxidative stress. FUTURE DIRECTIONS Loss of normal beta-cell function, rather than total mass, is increasingly considered to be the major driver for impaired insulin secretion in diabetes. Better understanding of the role of oxidative changes, its modulation by genes involved in disease risk, and effects on beta-cell identity may facilitate the development of new therapeutic strategies to this disease. Antioxid. Redox Signal. 26, 501-518.
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Affiliation(s)
- Philipp A. Gerber
- Department of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Zurich, Zurich, Switzerland
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Department of Medicine, Imperial College London, London, United Kingdom
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49
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Isaacs CJ, Brigatti KW, Kucheruk O, Ratcliffe S, Sciascia T, McCormack SE, Willi SM, Lynch DR. Effects of genetic severity on glucose homeostasis in Friedreich ataxia. Muscle Nerve 2016; 54:887-894. [PMID: 27061687 PMCID: PMC5257251 DOI: 10.1002/mus.25136] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/05/2016] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction. METHODS To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA. RESULTS Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanine-adenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and intravenous glucose loads. CONCLUSIONS FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient to patient. Muscle Nerve 54: 887-894, 2016.
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Affiliation(s)
- Charles J Isaacs
- Division of Neurology, The Children's Hospital of Philadelphia, 502 Abramson Research Center, Philadelphia, 3615 Civic Center Boulevard, Pennsylvania, 19104-4318, USA
| | - Karlla W Brigatti
- Division of Neurology, The Children's Hospital of Philadelphia, 502 Abramson Research Center, Philadelphia, 3615 Civic Center Boulevard, Pennsylvania, 19104-4318, USA
| | - Olena Kucheruk
- Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennyslvania, USA
| | - Sarah Ratcliffe
- Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennyslvania, USA
| | - Tom Sciascia
- Penwest Pharmaceuticals, New York, New York, USA
| | - Shana E McCormack
- Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennyslvania, USA
| | - Steven M Willi
- Division of Endocrinology/Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennyslvania, USA
| | - David R Lynch
- Division of Neurology, The Children's Hospital of Philadelphia, 502 Abramson Research Center, Philadelphia, 3615 Civic Center Boulevard, Pennsylvania, 19104-4318, USA.
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50
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Tamarit J, Obis È, Ros J. Oxidative stress and altered lipid metabolism in Friedreich ataxia. Free Radic Biol Med 2016; 100:138-146. [PMID: 27296838 DOI: 10.1016/j.freeradbiomed.2016.06.007] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 06/07/2016] [Accepted: 06/10/2016] [Indexed: 12/31/2022]
Abstract
Friedreich ataxia is a genetic disease caused by the deficiency of frataxin, a mitochondrial protein. Frataxin deficiency impacts in the cell physiology at several levels. One of them is oxidative stress with consequences in terms of protein dysfunctions and metabolic alterations. Among others, alterations in lipid metabolism have been observed in several models of the disease. In this review we summarize the current knowledge of the molecular basis of the disease, the relevance of oxidative stress and the therapeutic strategies based on reduction of mitochondrial reactive oxygen species production. Finally, we will focus the interest in alterations of lipid metabolism as a consequence of mitochondrial dysfunction and describe the therapeutic approaches based on targeting lipid metabolism.
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Affiliation(s)
- Jordi Tamarit
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain
| | - Èlia Obis
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain
| | - Joaquim Ros
- Departament de Ciències Mèdiques Bàsiques, IRB-Lleida, Universitat de Lleida, Lleida, Spain.
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