|
1
|
Vincow ES, Thomas RE, Milstein G, Pareek G, Bammler TK, MacDonald J, Pallanck LJ. Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation. PLoS Genet 2024; 20:e1011105. [PMID: 39527642 PMCID: PMC11581407 DOI: 10.1371/journal.pgen.1011105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 11/21/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024] Open
Abstract
Mutations in GBA (glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by GBA mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a Drosophila model of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressing Gba1b in activated macrophages suppressed head protein aggregation in Gba1b mutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also ameliorated Gba1b mutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.
Collapse
Affiliation(s)
- Evelyn S. Vincow
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Ruth E. Thomas
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Gillian Milstein
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Gautam Pareek
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Theo K. Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - James MacDonald
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - Leo J. Pallanck
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| |
Collapse
|
|
2
|
Şoroğlu CV, Berkay EG. Old disease-New reflections: Gaucher, immunity, and inflammation. J Cell Mol Med 2024; 28:e70087. [PMID: 39463025 PMCID: PMC11513444 DOI: 10.1111/jcmm.70087] [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: 10/16/2023] [Revised: 08/13/2024] [Accepted: 09/03/2024] [Indexed: 10/29/2024] Open
Abstract
Gaucher disease (GD) is the most common lysosomal storage disease. It is a multisystemic metabolic disease caused by GBA pathogenic mutations. Although the general symptoms have been known for a long time, new treatment possibilities, the detection of different biomarkers, and innovations in diagnosis and follow-up have paved the way for further studies. Recent studies have shown that the immune system has become an essential factor associated with disease progression. The role of Gaucher cells in the disease is well characterized. In addition to phagocytic macrophage cells, lymphocytes, complement system, and inflammatory pathway elements are also implicated in GD as they were shown to be the underlying factors causing associated pathologies such as Parkinson's. In this article, the relationship between the GD and the immune system has been examined and reviewed in light of new findings.
Collapse
Affiliation(s)
- Can Veysel Şoroğlu
- Department of Medical BiotechnologyAcıbadem Mehmet Ali Aydınlar University, Institute of Health SciencesIstanbulTurkey
| | - Ezgi Gizem Berkay
- Department of Basic Sciences, Dentistry FacultyIstanbul Kent UniversityIstanbulTurkey
| |
Collapse
|
|
3
|
Song S, Koh Y, Kim S, Lee SM, Kim HU, Ko JM, Lee SH, Yoon SS, Park S. Systematic analysis of Mendelian disease-associated gene variants reveals new classes of cancer-predisposing genes. Genome Med 2023; 15:107. [PMID: 38143269 PMCID: PMC10749499 DOI: 10.1186/s13073-023-01252-w] [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: 07/12/2023] [Accepted: 10/30/2023] [Indexed: 12/26/2023] Open
Abstract
BACKGROUND Despite the acceleration of somatic driver gene discovery facilitated by recent large-scale tumor sequencing data, the contribution of inherited variants remains largely unexplored, primarily focusing on previously known cancer predisposition genes (CPGs) due to the low statistical power associated with detecting rare pathogenic variant-phenotype associations. METHODS Here, we introduce a generalized log-regression model to measure the excess of pathogenic variants within genes in cancer patients compared to control samples. It aims to measure gene-level cancer risk enrichment by collapsing rare pathogenic variants after controlling the population differences across samples. RESULTS In this study, we investigate whether pathogenic variants in Mendelian disease-associated genes (OMIM genes) are enriched in cancer patients compared to controls. Utilizing data from PCAWG and the 1,000 Genomes Project, we identify 103 OMIM genes demonstrating significant enrichment of pathogenic variants in cancer samples (FDR 20%). Through an integrative approach considering three distinct properties, we classify these CPG-like OMIM genes into four clusters, indicating potential diverse mechanisms underlying tumor progression. Further, we explore the function of PAH (a key metabolic enzyme associated with Phenylketonuria), the gene exhibiting the highest prevalence of pathogenic variants in a pan-cancer (1.8%) compared to controls (0.6%). CONCLUSIONS Our findings suggest a possible cancer progression mechanism through metabolic profile alterations. Overall, our data indicates that pathogenic OMIM gene variants contribute to cancer progression and introduces new CPG classifications potentially underpinning diverse tumorigenesis mechanisms.
Collapse
Affiliation(s)
- Seulki Song
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Structural Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle de Melchor Fernández Almagro, 3, Madrid, 28029, Spain
| | - Youngil Koh
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
- Biomedical Research Institute and Departments of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea
| | - Seokhyeon Kim
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea
| | - Sang Mi Lee
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea
| | - Hyun Uk Kim
- Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, 34141, Republic of Korea.
| | - Jung Min Ko
- Department of Pediatrics, Seoul National University Children's Hospital, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
| | - Se-Hoon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Republic of Korea.
| | - Sung-Soo Yoon
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea.
- Biomedical Research Institute and Departments of Internal Medicine, Seoul National University Hospital, Seoul, 03080, Republic of Korea.
| | - Solip Park
- Structural Biology Program, Centro Nacional de Investigaciones Oncológicas (CNIO), Calle de Melchor Fernández Almagro, 3, Madrid, 28029, Spain.
| |
Collapse
|
|
4
|
Vincow ES, Thomas RE, Milstein G, Pareek G, Bammler T, MacDonald J, Pallanck L. Glucocerebrosidase deficiency leads to neuropathology via cellular immune activation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.12.13.571406. [PMID: 38168223 PMCID: PMC10760128 DOI: 10.1101/2023.12.13.571406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2024]
Abstract
Mutations in GBA (glucosylceramidase beta), which encodes the lysosomal enzyme glucocerebrosidase (GCase), are the strongest genetic risk factor for the neurodegenerative disorders Parkinson's disease (PD) and Lewy body dementia. Recent work has suggested that neuroinflammation may be an important factor in the risk conferred by GBA mutations. We therefore systematically tested the contributions of immune-related genes to neuropathology in a Drosophila model of GCase deficiency. We identified target immune factors via RNA-Seq and proteomics on heads from GCase-deficient flies, which revealed both increased abundance of humoral factors and increased macrophage activation. We then manipulated the identified immune factors and measured their effect on head protein aggregates, a hallmark of neurodegenerative disease. Genetic ablation of humoral (secreted) immune factors did not suppress the development of protein aggregation. By contrast, re-expressing Gba1b in activated macrophages suppressed head protein aggregation in Gba1b mutants and rescued their lifespan and behavioral deficits. Moreover, reducing the GCase substrate glucosylceramide in activated macrophages also ameliorated Gba1b mutant phenotypes. Taken together, our findings show that glucosylceramide accumulation due to GCase deficiency leads to macrophage activation, which in turn promotes the development of neuropathology.
Collapse
Affiliation(s)
- Evelyn S. Vincow
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Ruth E. Thomas
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Gillian Milstein
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Gautam Pareek
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| | - Theo Bammler
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - James MacDonald
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington, United States of America
| | - Leo Pallanck
- Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America
| |
Collapse
|
|
5
|
de Fàbregues O, Sellés M, Ramos-Vicente D, Roch G, Vila M, Bové J. Relevance of tissue-resident memory CD8 T cells in the onset of Parkinson's disease and examination of its possible etiologies: infectious or autoimmune? Neurobiol Dis 2023; 187:106308. [PMID: 37741513 DOI: 10.1016/j.nbd.2023.106308] [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: 12/16/2022] [Revised: 05/05/2023] [Accepted: 09/20/2023] [Indexed: 09/25/2023] Open
Abstract
Tissue-resident memory CD8 T cells are responsible for local immune surveillance in different tissues, including the brain. They constitute the first line of defense against pathogens and cancer cells and play a role in autoimmunity. A recently published study demonstrated that CD8 T cells with markers of residency containing distinct granzymes and interferon-γ infiltrate the parenchyma of the substantia nigra and contact dopaminergic neurons in an early premotor stage of Parkinson's disease. This infiltration precedes α-synuclein aggregation and neuronal loss in the substantia nigra, suggesting a relevant role for CD8 T cells in the onset of the disease. To date, the nature of the antigen that initiates the adaptive immune response remains unknown. This review will discuss the role of tissue-resident memory CD8 T cells in brain immune homeostasis and in the onset of Parkinson's disease and other neurological diseases. We also discuss how aging and genetic factors can affect the CD8 T cell immune response and how animal models can be misleading when studying human-related immune response. Finally, we speculate about a possible infectious or autoimmune origin of Parkinson's disease.
Collapse
Affiliation(s)
- Oriol de Fàbregues
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain; Movement Disorders Unit, Neurology Department, Vall d'Hebron University Hospital
| | - Maria Sellés
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain
| | - David Ramos-Vicente
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain
| | - Gerard Roch
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain
| | - Miquel Vila
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain; Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Catalonia, Spain; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain
| | - Jordi Bové
- Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Catalonia, Spain.
| |
Collapse
|
|
6
|
Mahé M, Rios-Fuller TJ, Karolin A, Schneider RJ. Genetics of enzymatic dysfunctions in metabolic disorders and cancer. Front Oncol 2023; 13:1230934. [PMID: 37601653 PMCID: PMC10433910 DOI: 10.3389/fonc.2023.1230934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 07/19/2023] [Indexed: 08/22/2023] Open
Abstract
Inherited metabolic disorders arise from mutations in genes involved in the biogenesis, assembly, or activity of metabolic enzymes, leading to enzymatic deficiency and severe metabolic impairments. Metabolic enzymes are essential for the normal functioning of cells and are involved in the production of amino acids, fatty acids and nucleotides, which are essential for cell growth, division and survival. When the activity of metabolic enzymes is disrupted due to mutations or changes in expression levels, it can result in various metabolic disorders that have also been linked to cancer development. However, there remains much to learn regarding the relationship between the dysregulation of metabolic enzymes and metabolic adaptations in cancer cells. In this review, we explore how dysregulated metabolism due to the alteration or change of metabolic enzymes in cancer cells plays a crucial role in tumor development, progression, metastasis and drug resistance. In addition, these changes in metabolism provide cancer cells with a number of advantages, including increased proliferation, resistance to apoptosis and the ability to evade the immune system. The tumor microenvironment, genetic context, and different signaling pathways further influence this interplay between cancer and metabolism. This review aims to explore how the dysregulation of metabolic enzymes in specific pathways, including the urea cycle, glycogen storage, lysosome storage, fatty acid oxidation, and mitochondrial respiration, contributes to the development of metabolic disorders and cancer. Additionally, the review seeks to shed light on why these enzymes represent crucial potential therapeutic targets and biomarkers in various cancer types.
Collapse
Affiliation(s)
| | | | | | - Robert J. Schneider
- Department of Microbiology, Grossman NYU School of Medicine, New York, NY, United States
| |
Collapse
|
|
7
|
Uzen R, Bayram F, Dursun H, Kardas F, Cakir M, Cucer N, Eken A, Donmez-Altuntas H. Characterization of peripheral blood T follicular helper (TFH) cells in patients with type 1 Gaucher disease and carriers. Blood Cells Mol Dis 2023; 100:102728. [PMID: 36738539 DOI: 10.1016/j.bcmd.2023.102728] [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: 10/06/2022] [Revised: 01/25/2023] [Accepted: 01/25/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Gaucher disease (GD) is the most common autosomal recessive lipid storage disease. In this study, the changes in TFH cells and IL-4 and IL-21 cytokines in blood samples of GD patients, carriers and healthy volunteers were investigated. METHODS Two pretreatment type 1 GD patients, 20 currently treated type 1 GD patients, 6 carriers, and 27 healthy volunteers were enrolled in the study. TFH cell (CD45RA-CD4+CXCR5+) number, phenotype (PD1, ICOS expression), and cytokine production (IL-21, IL-4) were assessed via flow cytometric assays. RESULTS No significant differences were found between the groups with respect to the number, frequency and PD1 or ICOS expression of TFH cells between healthy controls, patients and carriers. However, IL-4+ TFH cells were significantly reduced both in percent and number in the treated GD patients compared with healthy controls (p < 0.05). Interestingly, the IL-21+ TFH cell number was increased in treated GD patients. When TFH cells were examined based on CXCR3 expression, the frequency of the PD1+Th17-Th2-like fraction (CXCR3-) was found to be significantly increased in treated GD patients. CONCLUSION To our knowledge, this is the first study to assess TFH cells in GD patients, and to show that the production of IL-4 and IL-21 by TFH cells and their subsets may be altered in type 1 GD patients.
Collapse
Affiliation(s)
- Ramazan Uzen
- Department of Medical Biology, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey; 100/2000 CoHE PhD Scholarship Program, Institute of Health Sciences, Turkey.
| | - Fahri Bayram
- Department of Endocrinology and Metabolism, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey
| | - Huseyin Dursun
- Department of Endocrinology and Metabolism, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey
| | - Fatih Kardas
- Department of Pediatric Nutrition and Metabolism, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey
| | - Mustafa Cakir
- Department of Medical Biology, Medical Faculty, Van Yuzuncu Yıl University, 65080 Van, Turkey
| | - Nurhan Cucer
- Department of Medical Biology, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey
| | - Ahmet Eken
- Department of Medical Biology, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey; Betül-Ziya Eren Genome and Stem Cell Research Center, Erciyes University, 38030 Kayseri, Turkey
| | - Hamiyet Donmez-Altuntas
- Department of Medical Biology, Medical Faculty, Erciyes University, 38030 Kayseri, Turkey; Betül-Ziya Eren Genome and Stem Cell Research Center, Erciyes University, 38030 Kayseri, Turkey
| |
Collapse
|
|
8
|
Hemostatic Abnormalities in Gaucher Disease: Mechanisms and Clinical Implications. J Clin Med 2022; 11:jcm11236920. [PMID: 36498496 PMCID: PMC9735904 DOI: 10.3390/jcm11236920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/08/2022] [Accepted: 11/20/2022] [Indexed: 11/25/2022] Open
Abstract
Gaucher disease (GD) is a rare inherited lysosomal metabolism disorder, characterized by an accumulation into lysosomes of reticuloendothelial cells, especially in the bone marrow, spleen, and liver of β-glucosylceramide and glucosyl sphingosine, which is its deacylated product. Impaired storage is responsible for a chronic inflammatory state at the sites of accumulation and together represents the pathophysiological cause of GD. GD is a progressive, multi-organ chronic disorder. Type 1 GD is the most prevalent form, with heterogeneous multisystem involvement and different severity of symptoms at any age. Hematological involvement is consistent, and a bleeding tendency is frequent, particularly at diagnosis. Several coagulation and primary hemostasis abnormalities are observed in GD. Bleeding manifestations are rarely severe and usually mucocutaneous. Post-operative, delivery, and post-partum hemorrhages are also common. Thrombocytopenia, platelet function defects, and clotting abnormalities, alone or variably associated, contribute to increase the risk of bleeding in GD. Enzyme replacement therapy (ERT) or substrate reduction therapy (SRT) are the two specific available treatments effective in improving typical hematological symptoms and abnormalities, including those of hemostasis. However, the use of medication to potentiate hemostasis may be also useful in defined clinical situations: recent starting of ERT/SRT, surgery, delivery, and life-threatening bleeding.
Collapse
|
|
9
|
Lundregan SL, Mäkinen H, Buer A, Holand H, Jensen H, Husby A. Infection by a helminth parasite is associated with changes in DNA methylation in the house sparrow. Ecol Evol 2022; 12:e9539. [PMID: 36447599 PMCID: PMC9702581 DOI: 10.1002/ece3.9539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 10/24/2022] [Accepted: 11/03/2022] [Indexed: 11/29/2022] Open
Abstract
Parasites can exert strong selective pressures on their hosts and influence the evolution of host immunity. While several studies have examined the genetic basis for parasite resistance, the role of epigenetics in the immune response to parasites is less understood. Yet, epigenetic modifications, such as changes in DNA methylation, may allow species to respond rapidly to parasite prevalence or virulence. To test the role of DNA methylation in relation to parasite infection, we examined genome-wide DNA methylation before and during infection by a parasitic nematode, Syngamus trachea, in a natural population of house sparrows (Passer domesticus) using reduced representation bisulfite sequencing (RRBS). We found that DNA methylation levels were slightly lower in infected house sparrows, and we identified candidate genes relating to the initial immune response, activation of innate and adaptive immunity, and mucus membrane functional integrity that were differentially methylated between infected and control birds. Subsequently, we used methylation-sensitive high-resolution melting (MS-HRM) analyses to verify the relationship between methylation proportion and S. trachea infection status at two candidate genes in a larger sample dataset. We found that methylation level at NR1D1, but not CLDN22, remained related to infection status and that juvenile recruitment probability was positively related to methylation level at NR1D1. This underscores the importance of performing follow-up studies on candidate genes. Our findings demonstrate that plasticity in the immune response to parasites can be epigenetically mediated and highlight the potential for epigenetic studies in natural populations to provide further mechanistic insight into host-parasite interactions.
Collapse
Affiliation(s)
- Sarah L. Lundregan
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
| | - Hannu Mäkinen
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
- Evolutionary Biology, Department of Ecology and GeneticsUppsala UniversityUppsalaSweden
| | - Amberly Buer
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
| | - Håkon Holand
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
| | - Henrik Jensen
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
| | - Arild Husby
- Department of Biology, Centre for Biodiversity DynamicsNorwegian University of Science and TechnologyTrondheimNorway
- Evolutionary Biology, Department of Ecology and GeneticsUppsala UniversityUppsalaSweden
| |
Collapse
|
|
10
|
Heavener KS, Bradshaw EM. The aging immune system in Alzheimer's and Parkinson's diseases. Semin Immunopathol 2022; 44:649-657. [PMID: 35505128 PMCID: PMC9519729 DOI: 10.1007/s00281-022-00944-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 04/20/2022] [Indexed: 11/03/2022]
Abstract
The neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) both have a myriad of risk factors including genetics, environmental exposures, and lifestyle. However, aging is the strongest risk factor for both diseases. Aging also profoundly influences the immune system, with immunosenescence perhaps the most prominent outcome. Through genetics, mouse models, and pathology, there is a growing appreciation of the role the immune system plays in neurodegenerative diseases. In this review, we explore the intersection of aging and the immune system in AD and PD.
Collapse
Affiliation(s)
- Kelsey S Heavener
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Elizabeth M Bradshaw
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, 10032, USA.
| |
Collapse
|
|
11
|
Lunghi G, Carsana EV, Loberto N, Cioccarelli L, Prioni S, Mauri L, Bassi R, Duga S, Straniero L, Asselta R, Soldà G, Di Fonzo A, Frattini E, Magni M, Liessi N, Armirotti A, Ferrari E, Samarani M, Aureli M. β-Glucocerebrosidase Deficiency Activates an Aberrant Lysosome-Plasma Membrane Axis Responsible for the Onset of Neurodegeneration. Cells 2022; 11:cells11152343. [PMID: 35954187 PMCID: PMC9367513 DOI: 10.3390/cells11152343] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/25/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
β-glucocerebrosidase is a lysosomal hydrolase involved in the catabolism of the sphingolipid glucosylceramide. Biallelic loss of function mutations in this enzyme are responsible for the onset of Gaucher disease, while monoallelic β-glucocerebrosidase mutations represent the first genetic risk factor for Parkinson’s disease. Despite this evidence, the molecular mechanism linking the impairment in β-glucocerebrosidase activity with the onset of neurodegeneration in still unknown. In this frame, we developed two in vitro neuronal models of β-glucocerebrosidase deficiency, represented by mouse cerebellar granule neurons and human-induced pluripotent stem cells-derived dopaminergic neurons treated with the specific β-glucocerebrosidase inhibitor conduritol B epoxide. Neurons deficient for β-glucocerebrosidase activity showed a lysosomal accumulation of glucosylceramide and the onset of neuronal damage. Moreover, we found that neurons react to the lysosomal impairment by the induction of their biogenesis and exocytosis. This latter event was responsible for glucosylceramide accumulation also at the plasma membrane level, with an alteration in lipid and protein composition of specific signaling microdomains. Collectively, our data suggest that β-glucocerebrosidase loss of function impairs the lysosomal compartment, establishing a lysosome–plasma membrane axis responsible for modifications in the plasma membrane architecture and possible alterations of intracellular signaling pathways, leading to neuronal damage.
Collapse
Affiliation(s)
- Giulia Lunghi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Emma Veronica Carsana
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Nicoletta Loberto
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Laura Cioccarelli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Simona Prioni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Laura Mauri
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Rosaria Bassi
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
| | - Stefano Duga
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (S.D.); (L.S.); (R.A.); (G.S.)
- Humanitas Clinical and Research Center—IRCCS, Via Manzoni 56, 20072 Milan, Italy
| | - Letizia Straniero
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (S.D.); (L.S.); (R.A.); (G.S.)
- Humanitas Clinical and Research Center—IRCCS, Via Manzoni 56, 20072 Milan, Italy
| | - Rosanna Asselta
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (S.D.); (L.S.); (R.A.); (G.S.)
- Humanitas Clinical and Research Center—IRCCS, Via Manzoni 56, 20072 Milan, Italy
| | - Giulia Soldà
- Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy; (S.D.); (L.S.); (R.A.); (G.S.)
- Humanitas Clinical and Research Center—IRCCS, Via Manzoni 56, 20072 Milan, Italy
| | - Alessio Di Fonzo
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (A.D.F.); (E.F.); (M.M.)
| | - Emanuele Frattini
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (A.D.F.); (E.F.); (M.M.)
| | - Manuela Magni
- IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy; (A.D.F.); (E.F.); (M.M.)
| | - Nara Liessi
- Analytical Chemistry Facility, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; (N.L.); (A.A.)
| | - Andrea Armirotti
- Analytical Chemistry Facility, Fondazione Istituto Italiano di Tecnologia, Via Morego 30, 16163 Genoa, Italy; (N.L.); (A.A.)
| | - Elena Ferrari
- Department of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy;
| | - Maura Samarani
- Department of Cell Biology and Infection, Institut Pasteur, 75015 Paris, France;
| | - Massimo Aureli
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20054 Milan, Italy; (G.L.); (E.V.C.); (N.L.); (L.C.); (S.P.); (L.M.); (R.B.)
- Correspondence: ; Tel.: +39-025-033-0364
| |
Collapse
|
|
12
|
Mamais A, Kaganovich A, Harvey K. Convergence of signalling pathways in innate immune responses and genetic forms of Parkinson's disease. Neurobiol Dis 2022; 169:105721. [PMID: 35405260 DOI: 10.1016/j.nbd.2022.105721] [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: 12/03/2021] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 10/18/2022] Open
Abstract
In recent years progress in molecular biology and genetics have advanced our understanding of neurological disorders and highlighted synergistic relationships with inflammatory and age-related processes. Parkinson's disease (PD) is a common neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Increasing extensive evidence supports the contribution of genetic risk variants and inflammation in the pathobiology of this disease. Functional and genetic studies demonstrate an overlap between genes linked to increased risk for PD and autoimmune diseases. Variants identified in loci adjacent to LRRK2, GBA, and HLA establish a crosstalk between the pathobiologies of the two disease spectra. Furthermore, common signalling pathways associated with the pathogenesis of genetic PD are also relevant to inflammatory signaling include MAPK, NF-κB, Wnt and inflammasome signaling. Importantly, post-mortem analyses of brain and cerebrospinal fluid from PD patients show the accumulation of proinflammatory cytokines. In this review we will focus on the principal mechanisms of genetic, inflammatory and age-related risk that intersect in the pathogenesis of PD.
Collapse
Affiliation(s)
- Adamantios Mamais
- Department of Neurology, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Alice Kaganovich
- Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kirsten Harvey
- Department of Pharmacology, UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK..
| |
Collapse
|
|
13
|
Kasen A, Houck C, Burmeister AR, Sha Q, Brundin L, Brundin P. Upregulation of α-synuclein following immune activation: Possible trigger of Parkinson's disease. Neurobiol Dis 2022; 166:105654. [DOI: 10.1016/j.nbd.2022.105654] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 12/20/2022] Open
|
|
14
|
Roh J, Subramanian S, Weinreb NJ, Kartha RV. Gaucher disease – more than just a rare lipid storage disease. J Mol Med (Berl) 2022; 100:499-518. [DOI: 10.1007/s00109-021-02174-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 10/29/2021] [Accepted: 12/06/2021] [Indexed: 01/18/2023]
|
|
15
|
Magnusen AF, Rani R, McKay MA, Hatton SL, Nyamajenjere TC, Magnusen DNA, Köhl J, Grabowski GA, Pandey MK. C-X-C Motif Chemokine Ligand 9 and Its CXCR3 Receptor Are the Salt and Pepper for T Cells Trafficking in a Mouse Model of Gaucher Disease. Int J Mol Sci 2021; 22:ijms222312712. [PMID: 34884512 PMCID: PMC8657559 DOI: 10.3390/ijms222312712] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 11/08/2021] [Accepted: 11/18/2021] [Indexed: 02/07/2023] Open
Abstract
Gaucher disease is a lysosomal storage disease, which happens due to mutations in GBA1/Gba1 that encodes the enzyme termed as lysosomal acid β-glucosidase. The major function of this enzyme is to catalyze glucosylceramide (GC) into glucose and ceramide. The deficiency of this enzyme and resultant abnormal accumulation of GC cause altered function of several of the innate and adaptive immune cells. For example, augmented infiltration of T cells contributes to the increased production of pro-inflammatory cytokines, (e.g., IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F). This leads to tissue damage in a genetic mouse model (Gba19V/-) of Gaucher disease. The cellular mechanism(s) by which increased tissue infiltration of T cells occurs in this disease is not fully understood. Here, we delineate role of the CXCR3 receptor and its exogenous C-X-C motif chemokine ligand 9 (CXCL9) in induction of increased tissue recruitment of CD4+ T and CD8+ T cells in Gaucher disease. Intracellular FACS staining of macrophages (Mϕs) and dendritic cells (DCs) from Gba19V/- mice showed elevated production of CXCL9. Purified CD4+ T cells and the CD8+ T cells from Gba19V/- mice showed increased expression of CXCR3. Ex vivo and in vivo chemotaxis experiments showed CXCL9 involvement in the recruitment of Gba19V/- T cells. Furthermore, antibody blockade of the CXCL9 receptor (CXCR3) on T cells caused marked reduction in CXCL9- mediated chemotaxis of T cells in Gba19V/- mice. These data implicate abnormalities of the CXCL9-CXCR3 axis leading to enhanced tissue recruitment of T cells in Gaucher disease. Such results provide a rationale for blockade of the CXCL9/CXCR3 axis as potential new therapeutic targets for the treatment of inflammation in Gaucher disease.
Collapse
Affiliation(s)
- Albert Frank Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Reena Rani
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA;
| | - Mary Ashley McKay
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Shelby Loraine Hatton
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Tsitsi Carol Nyamajenjere
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Daniel Nii Aryee Magnusen
- Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA; (A.F.M.); (M.A.M.); (S.L.H.); (T.C.N.); (D.N.A.M.)
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, 23562 Lübeck, Germany;
- Department of Pediatrics and Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Gregory Alex Grabowski
- Department of Molecular Genetics, Biochemistry and Microbiology, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA;
- Department of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
| | - Manoj Kumar Pandey
- Department of Pediatrics, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, College of Medicine, University of Cincinnati, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
- Correspondence:
| |
Collapse
|
|
16
|
Decreased glucocerebrosidase activity and substrate accumulation of glycosphingolipids in a novel GBA1 D409V knock-in mouse model. PLoS One 2021; 16:e0252325. [PMID: 34106956 PMCID: PMC8189458 DOI: 10.1371/journal.pone.0252325] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 05/13/2021] [Indexed: 11/30/2022] Open
Abstract
Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher’s disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson’s disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms and novel therapeutic approaches, as well as to elucidate the molecular mechanisms leading to enhanced PD risk in GBA1 mutation carriers. The aim of this study was to develop and characterize a novel GBA1 mouse model and to facilitate wide accessibility of the model with phenotypic data. Herein we describe the results of molecular, biochemical, histological, and behavioral phenotyping analyses in a GBA1 D409V knock-in (KI) mouse. This mouse model exhibited significantly decreased GCase activity in liver and brain, with substantial increases in glycosphingolipid substrates in the liver. While no changes in the number of dopamine neurons in the substantia nigra were noted, subtle changes in striatal neurotransmitters were observed in GBA1 D409V KI mice. Alpha-synuclein pathology and inflammation were not observed in the nigrostriatal system of this model. In summary, the GBA1 D409V KI mouse model provides an ideal model for studies aimed at pharmacodynamic assessments of potential therapies aiming to restore GCase.
Collapse
|
|
17
|
Galper J, Balwani M, Fahn S, Waters C, Krohn L, Gan-Or Z, Dzamko N, Alcalay RN. Cytokines and Gaucher Biomarkers in Glucocerebrosidase Carriers with and Without Parkinson Disease. Mov Disord 2021; 36:1451-1455. [PMID: 33570220 PMCID: PMC8248172 DOI: 10.1002/mds.28525] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/22/2020] [Accepted: 01/19/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Homozygous and compound heterozygous variants in glucocerebrosidase (GBA) can cause Gaucher disease (GD), whereas heterozygous variants increase the risk of developing Parkinson's disease (PD). GD patients display altered peripheral immune proteins. However, it is unknown if these are altered in GBA carriers with PD. OBJECTIVES To determine whether plasma cytokines and immune biomarkers associated with GD are also altered in GBA carriers with or without PD. METHODS Inflammatory cytokines and established GD biomarkers, ferritin, CD162, CCL18, and chitotriosidase (28 biomarkers) were measured in GBA pathogenic variant carriers with (n = 135) and without (n = 83) PD, and non-carriers with (n = 75) and without PD (n = 77). RESULTS PD patients with biallelic pathogenic variants in GBA had elevated plasma levels of ferritin, CCL18, and MIP1α. These biomarkers were not elevated in heterozygous GBA carriers. CONCLUSION GD plasma biomarkers are not promising candidates for stratifying the risk for PD in carriers of heterozygous GBA pathogenic variants. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Collapse
Affiliation(s)
- Jasmin Galper
- Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia
| | - Manisha Balwani
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Stanley Fahn
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Cheryl Waters
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
| | - Lynne Krohn
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada.,The Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Ziv Gan-Or
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada.,The Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.,Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada
| | - Nicolas Dzamko
- Brain and Mind Centre and Faculty of Medicine and Health, School of Medical Sciences, University of Sydney, Camperdown, New South Wales, Australia
| | - Roy N Alcalay
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA
| |
Collapse
|
|
18
|
Grabowski GA, Antommaria AHM, Kolodny EH, Mistry PK. Gaucher disease: Basic and translational science needs for more complete therapy and management. Mol Genet Metab 2021; 132:59-75. [PMID: 33419694 PMCID: PMC8809485 DOI: 10.1016/j.ymgme.2020.12.291] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 11/15/2020] [Accepted: 12/18/2020] [Indexed: 12/12/2022]
Affiliation(s)
- Gregory A Grabowski
- Department of Pediatrics, University of Cincinnati College of Medicine, United States of America; Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, United States of America; Division of Human Genetics, Cincinnati Children's Research Foundation, Cincinnati, OH, United States of America.
| | - Armand H M Antommaria
- Department of Pediatrics, University of Cincinnati College of Medicine, United States of America; Lee Ault Carter Chair of Pediatric Ethics, Cincinnati Children's Research Foundation, Cincinnati, OH, United States of America.
| | - Edwin H Kolodny
- Department of Neurology, New York University Grossman School of Medicine, New York, NY, United States of America.
| | - Pramod K Mistry
- Departments of Medicine and Pediatrics, Yale School of Medicine, New Haven, CT, United States of America.
| |
Collapse
|
|
19
|
von Linstow CU, Gan-Or Z, Brundin P. Precision medicine in Parkinson's disease patients with LRRK2 and GBA risk variants - Let's get even more personal. Transl Neurodegener 2020; 9:39. [PMID: 33066808 PMCID: PMC7565766 DOI: 10.1186/s40035-020-00218-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/22/2020] [Indexed: 12/15/2022] Open
Abstract
Parkinson's disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove "precise" or "personalized" enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.
Collapse
Affiliation(s)
| | - Ziv Gan-Or
- Montreal Neurological Institute, McGill University, Montréal, QC, H3A 2B4, Canada.,Department of Human Genetics, McGill University, Montréal, QC, H3A 0C7, Canada.,Department of Neurology and Neurosurgery, McGill University, Montréal, QC, H3A 2B4, Canada
| | - Patrik Brundin
- Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA
| |
Collapse
|
|
20
|
Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review. Int J Mol Sci 2020; 21:ijms21197159. [PMID: 32998334 PMCID: PMC7584006 DOI: 10.3390/ijms21197159] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/17/2022] Open
Abstract
The challenges in the diagnosis, prognosis, and monitoring of Gaucher disease (GD), an autosomal recessive inborn error of glycosphingolipid metabolism, can negatively impact clinical outcomes. This systematic literature review evaluated the value of glucosylsphingosine (lyso-Gb1), as the most reliable biomarker currently available for the diagnosis, prognosis, and disease/treatment monitoring of patients with GD. Literature searches were conducted using MEDLINE, Embase, PubMed, ScienceOpen, Science.gov, Biological Abstracts, and Sci-Hub to identify original research articles relevant to lyso-Gb1 and GD published before March 2019. Seventy-four articles met the inclusion criteria, encompassing 56 related to pathology and 21 related to clinical biomarkers. Evidence for lyso-Gb1 as a pathogenic mediator of GD was unequivocal, although its precise role requires further elucidation. Lyso-Gb1 was deemed a statistically reliable diagnostic and pharmacodynamic biomarker in GD. Evidence supports lyso-Gb1 as a disease-monitoring biomarker for GD, and some evidence supports lyso-Gb1 as a prognostic biomarker, but further study is required. Lyso-Gb1 meets the criteria for a biomarker as it is easily accessible and reliably quantifiable in plasma and dried blood spots, enables the elucidation of GD molecular pathogenesis, is diagnostically valuable, and reflects therapeutic responses. Evidentiary standards appropriate for verifying inter-laboratory lyso-Gb1 concentrations in plasma and in other anatomical sites are needed.
Collapse
|
|
21
|
Dupuis L, Chipeaux C, Bourdelier E, Martino S, Reihani N, Belmatoug N, Billette de Villemeur T, Hivert B, Moussa F, Le Van Kim C, de Person M, Franco M. Effects of sphingolipids overload on red blood cell properties in Gaucher disease. J Cell Mol Med 2020; 24:9726-9736. [PMID: 32767726 PMCID: PMC7520281 DOI: 10.1111/jcmm.15534] [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: 04/05/2020] [Revised: 05/22/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
Gaucher disease (GD) is a genetic disease with mutations in the GBA gene that encodes glucocerebrosidase causing complications such as anaemia and bone disease. GD is characterized by accumulation of the sphingolipids (SL) glucosylceramide (GL1), glucosylsphingosine (Lyso‐GL1), sphingosine (Sph) and sphingosine‐1‐phosphate (S1P). These SL are increased in the plasma of GD patients and the associated complications have been attributed to the accumulation of lipids in macrophages. Our recent findings indicated that red blood cells (RBCs) and erythroid progenitors may play an important role in GD pathophysiology. RBCs abnormalities and dyserythropoiesis have been observed in GD patients. Moreover, we showed higher SL levels in the plasma and in RBCs from untreated GD patients compared with controls. In this study, we quantified SL in 16 untreated GD patients and 15 patients treated with enzyme replacement therapy. Our results showed that the treatment significantly decreases SL levels in the plasma and RBCs. The increased SL content in RBCs correlates with abnormal RBC properties and with markers of disease activity. Because RBCs lack glucocerebrosidase activity, we investigated how lipid overload could occur in these cells. Our results suggested that SL overload in RBCs occurs both during erythropoiesis and during its circulation in the plasma.
Collapse
Affiliation(s)
- Lucie Dupuis
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| | - Caroline Chipeaux
- CNRS, Institut de Chimie Physique, UMR 8000, Université Paris-Saclay, Orsay, France
| | - Emmanuelle Bourdelier
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| | - Suella Martino
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| | - Nelly Reihani
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| | - Nadia Belmatoug
- AP-HP, CRML Maladies Lysosomales, Service de Médecine Interne, Hôpital Beaujon, Université de Paris, Clichy, France
| | | | - Bénédicte Hivert
- Service d'Hématologie, Hôpital Saint Vincent de Paul, GHICL, Lille, France
| | - Fathi Moussa
- CNRS, Institut de Chimie Physique, UMR 8000, Université Paris-Saclay, Orsay, France
| | - Caroline Le Van Kim
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| | - Marine de Person
- CNRS, Institut de Chimie Physique, UMR 8000, Université Paris-Saclay, Orsay, France
| | - Mélanie Franco
- UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire d'Excellence GR-Ex, Université de Paris, Paris, France
| |
Collapse
|
|
22
|
Franco M, Reihani N, Dupuis L, Collec E, Billette de Villemeur T, Person M, Moussa F, Berger MG, Belmatoug N, Le Van Kim C. Semaphorin 7A: A novel marker of disease activity in Gaucher disease. Am J Hematol 2020; 95:483-491. [PMID: 31990411 DOI: 10.1002/ajh.25744] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 01/16/2020] [Accepted: 01/21/2020] [Indexed: 01/13/2023]
Abstract
Gaucher disease (GD) is a recessively inherited lysosomal storage disorder in which sphingolipids accumulates in the macrophages that transform into Gaucher cells. A growing body of evidence indicates that red blood cells (RBCs) represent important actors in GD pathophysiology. We previously demonstrated that altered RBC properties including increased Lyso-GL1 levels, dyserythropoiesis, and iron metabolism defect in GD patients contribute to anemia and hyperferritinemia. Since RBC defects also correlated well with markers of GD severity and were normalized under enzyme replacement therapy (ERT), the identification of molecules that are deregulated in GD RBCs represents an important issue in the search of pertinent markers of the disease. Here, we found a decreased expression of the GPI-anchored cell surface protein Semaphorin 7A (Sema7A) in RBCs from untreated GD (GD UT) patients, in parallel with increased levels of the soluble form in the plasma. Sema7A plays a role in neural guidance, atherosclerosis, and inflammatory diseases and represents a promigratory cue in physiological and pathological conditions. We showed that the decreased expression of Sema7A in RBCs correlated with their abnormal properties and with markers of GD activity. Interestingly, ERT restored the level of Sema7A to normal values both in RBCs and in plasma from GD patients. We then proposed that SemaA7A represents a simple and pertinent marker of inflammation in GD. Finally, because Sema7A is known to regulate the activity of immune cells, the increased level of soluble Sema7A in GD patients could propagate inflammation in several tissues.
Collapse
Affiliation(s)
- Mélanie Franco
- Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire dʼExcellence GR‐Ex Paris France
| | - Nelly Reihani
- Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire dʼExcellence GR‐Ex Paris France
| | - Lucie Dupuis
- Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire dʼExcellence GR‐Ex Paris France
| | - Emmanuel Collec
- Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire dʼExcellence GR‐Ex Paris France
| | | | - Marine Person
- IUT Orsay, CNRS UMR 8000, Institut de Chimie Physique Orsay France
| | - Fathi Moussa
- IUT Orsay, CNRS UMR 8000, Institut de Chimie Physique Orsay France
| | - Marc G. Berger
- Université Clermont Auvergne, EA 7453 CHELTER Clermont‐Ferrand France
- CHU Clermont‐Ferrand, Service Hématologie Biologique, Hôpital Estaing Clermont‐Ferrand France
| | - Nadia Belmatoug
- Université de Paris, AP‐HP, CRML Maladies Lysosomales, Service de Médecine Interne, Hôpital Beaujon Clichy France
| | - Caroline Le Van Kim
- Université de Paris, UMR_S1134, BIGR, Inserm, Institut National de Transfusion Sanguine, Laboratoire dʼExcellence GR‐Ex Paris France
| |
Collapse
|
|
23
|
Are Glucosylceramide-Related Sphingolipids Involved in the Increased Risk for Cancer in Gaucher Disease Patients? Review and Hypotheses. Cancers (Basel) 2020; 12:cancers12020475. [PMID: 32085512 PMCID: PMC7072201 DOI: 10.3390/cancers12020475] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Revised: 01/31/2020] [Accepted: 02/14/2020] [Indexed: 01/19/2023] Open
Abstract
The roles of ceramide and its catabolites, i.e., sphingosine and sphingosine 1-phosphate, in the development of malignancies and the response to anticancer regimens have been extensively described. Moreover, an abundant literature points to the effects of glucosylceramide synthase, the mammalian enzyme that converts ceramide to β-glucosylceramide, in protecting tumor cells from chemotherapy. Much less is known about the contribution of β-glucosylceramide and its breakdown products in cancer progression. In this chapter, we first review published and personal clinical observations that report on the increased risk of developing cancers in patients affected with Gaucher disease, an inborn disorder characterized by defective lysosomal degradation of β-glucosylceramide. The previously described mechanistic links between lysosomal β-glucosylceramidase, β-glucosylceramide and/or β-glucosylphingosine, and various hallmarks of cancer are reviewed. We further show that melanoma tumor growth is facilitated in a Gaucher disease mouse model. Finally, the potential roles of the β-glucosylceramidase protein and its lipidic substrates and/or downstream products are discussed.
Collapse
|
|
24
|
Abstract
Kinase activating missense mutations in leucine-rich repeat kinase 2 (LRRK2) are pathogenically linked to neurodegenerative Parkinson's disease (PD). Over the past decade, substantial effort has been devoted to the development of potent and selective small molecule inhibitors of LRRK2, as well as their preclinical testing across different Parkinson's disease models. This review outlines the genetic and biochemical evidence that pathogenic missense mutations increase LRRK2 kinase activity, which in turn provides the rationale for the development of small molecule inhibitors as potential PD therapeutics. An overview of progress in the development of LRRK2 inhibitors is provided, which in particular indicates that highly selective and potent compounds capable of clinical utility have been developed. We outline evidence from rodent- and human-induced pluripotent stem cell models that support a pathogenic role for LRRK2 kinase activity, and review the substantial experiments aimed at evaluating the safety of LRRK2 inhibitors. We address challenges still to overcome in the translational therapeutic pipeline, including biomarker development and clinical trial strategies, and finally outline the potential utility of LRRK2 inhibitors for other genetic forms of PD and ultimately sporadic PD. Collective evidence supports the ongoing clinical translation of LRRK2 inhibitors as a therapeutic intervention for PD is greatly needed.
Collapse
|
|
25
|
Drosophila melanogaster Mutated in its GBA1b Ortholog Recapitulates Neuronopathic Gaucher Disease. J Clin Med 2019; 8:jcm8091420. [PMID: 31505865 PMCID: PMC6780790 DOI: 10.3390/jcm8091420] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Revised: 09/04/2019] [Accepted: 09/05/2019] [Indexed: 01/04/2023] Open
Abstract
Gaucher disease (GD) results from mutations in the GBA1 gene, which encodes lysosomal glucocerebrosidase (GCase). The large number of mutations known to date in the gene lead to a heterogeneous disorder, which is divided into a non-neuronopathic, type 1 GD, and two neurological, type 2 and type 3, forms. We studied the two fly GBA1 orthologs, GBA1a and GBA1b. Each contains a Minos element insertion, which truncates its coding sequence. In the GBA1am/m flies, which express a mutant protein, missing 33 C-terminal amino acids, there was no decrease in GCase activity or substrate accumulation. However, GBA1bm/m mutant flies presented a significant decrease in GCase activity with concomitant substrate accumulation, which included C14:1 glucosylceramide and C14:0 glucosylsphingosine. GBA1bm/m mutant flies showed activation of the Unfolded Protein Response (UPR) and presented inflammation and neuroinflammation that culminated in development of a neuronopathic disease. Treatment with ambroxol did not rescue GCase activity or reduce substrate accumulation; however, it ameliorated UPR, inflammation and neuroinflammation, and increased life span. Our results highlight the resemblance between the phenotype of the GBA1bm/m mutant fly and neuronopathic GD and underlie its relevance in further GD studies as well as a model to test possible therapeutic modalities.
Collapse
|
|
26
|
Insights into GBA Parkinson's disease pathology and therapy with induced pluripotent stem cell model systems. Neurobiol Dis 2019; 127:1-12. [DOI: 10.1016/j.nbd.2019.01.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/25/2019] [Accepted: 01/29/2019] [Indexed: 01/29/2023] Open
|
|
27
|
Vujosevic S, Medenica S, Vujicic V, Dapcevic M, Bakic N, Yang R, Liu J, Mistry PK. Gaucher disease in Montenegro - genotype/phenotype correlations: Five cases report. World J Clin Cases 2019; 7:1475-1482. [PMID: 31363476 PMCID: PMC6656677 DOI: 10.12998/wjcc.v7.i12.1475] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/01/2019] [Accepted: 05/11/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The most common lysosomal storage disorder is Gaucher disease (GD). It is a deficiency of lysosomal glucocerebrosidase (GBA) due to biallelic mutations in the GBA gene, characterized by the deposition of glucocerebroside in macrophage-monocyte system cells. The report targets clinical phenotypes of GD in order to correlate them with GBA gene mutations, as well as to identify GBA gene mutation in patients in Montenegro that are diagnosed with GD.
CASES SUMMARY Five patients (4 male, 1 female) of type 1 GD (GD1) are reported. The age at diagnosis ranged from 7 to 40. Patients experienced delays of 1-12 years in diagnosis after the original onset of symptoms. The most common mode of presentation was a variable degree of splenomegaly and thrombocytopenia, while other symptoms included bone pain, hepatomegaly, abdominal pain and fatigue. Osteopenia was present in a majority of the patients: 4/5. All patients were found to have an asymptomatic Erlenmeyer flask deformity of the distal femur. On enzyme replacement therapy (ERT), the hematological and visceral parameters showed significant improvement, but no significant progression in bone mineral density was noticed. GBA gene sequencing revealed homozygosity for the N370S mutation in one patient. The genotypes of the other patients were N370S/55bp deletion, N370S/D409H (2 patients), and H255Q/N370S (1 patient).
CONCLUSION The phenotypes of the GD1 encountered in Montenegro were severe but all responded well to ERT.
Collapse
Affiliation(s)
- Snezana Vujosevic
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Sanja Medenica
- Department of Endocrinology, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Vesko Vujicic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Milena Dapcevic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Nikola Bakic
- Hematology Department, Internal Medicine Clinic, Clinical Center of Montenegro, Faculty of Medicine, University of Montenegro, Podgorica 81000, Montenegro
| | - Ruhua Yang
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Jun Liu
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Pramod K Mistry
- Yale Lysosomal Disease Center and Inherited Metabolic Liver Disease Clinic, Yale University School of Medicine, New Haven, CT 06510, United States
| |
Collapse
|
|
28
|
Mechanism of glucocerebrosidase activation and dysfunction in Gaucher disease unraveled by molecular dynamics and deep learning. Proc Natl Acad Sci U S A 2019; 116:5086-5095. [PMID: 30808805 DOI: 10.1073/pnas.1818411116] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The lysosomal enzyme glucocerebrosidase-1 (GCase) catalyzes the cleavage of a major glycolipid glucosylceramide into glucose and ceramide. The absence of fully functional GCase leads to the accumulation of its lipid substrates in lysosomes, causing Gaucher disease, an autosomal recessive disorder that displays profound genotype-phenotype nonconcordance. More than 250 disease-causing mutations in GBA1, the gene encoding GCase, have been discovered, although only one of these, N370S, causes 70% of disease. Here, we have used a knowledge-based docking protocol that considers experimental data of protein-protein binding to generate a complex between GCase and its known facilitator protein saposin C (SAPC). Multiscale molecular-dynamics simulations were used to study lipid self-assembly, membrane insertion, and the dynamics of the interactions between different components of the complex. Deep learning was applied to propose a model that explains the mechanism of GCase activation, which requires SAPC. Notably, we find that conformational changes in the loops at the entrance of the substrate-binding site are stabilized by direct interactions with SAPC and that the loss of such interactions induced by N370S and another common mutation, L444P, result in destabilization of the complex and reduced GCase activation. Our findings provide an atomistic-level explanation for GCase activation and the precise mechanism through which N370S and L444P cause Gaucher disease.
Collapse
|
|
29
|
Nasrolahi A, Safari F, Farhoudi M, Khosravi A, Farajdokht F, Bastaminejad S, Sandoghchian Shotorbani S, Mahmoudi J. Immune system and new avenues in Parkinson’s disease research and treatment. Rev Neurosci 2019; 30:709-727. [DOI: 10.1515/revneuro-2018-0105] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 12/28/2018] [Indexed: 12/13/2022]
Abstract
Abstract
Parkinson’s disease (PD) is a progressive neurological disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. However, although 200 years have now passed since the primary clinical description of PD by James Parkinson, the etiology and mechanisms of neuronal loss in this disease are still not fully understood. In addition to genetic and environmental factors, activation of immunologic responses seems to have a crucial role in PD pathology. Intraneuronal accumulation of α-synuclein (α-Syn), as the main pathological hallmark of PD, potentially mediates initiation of the autoimmune and inflammatory events through, possibly, auto-reactive T cells. While current therapeutic regimens are mainly used to symptomatically suppress PD signs, application of the disease-modifying therapies including immunomodulatory strategies may slow down the progressive neurodegeneration process of PD. The aim of this review is to summarize knowledge regarding previous studies on the relationships between autoimmune reactions and PD pathology as well as to discuss current opportunities for immunomodulatory therapy.
Collapse
Affiliation(s)
- Ava Nasrolahi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences , Tabriz 51666-14756 , Iran
- Department of Molecular Medicine, Faculty of Advanced Medical Sciences , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Fatemeh Safari
- Departmant of Medical Biotechnology, School of Advanced Medical Sciences and Technologies , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Mehdi Farhoudi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences , Tabriz 51666-14756 , Iran
| | - Afra Khosravi
- Department of Immunology, Faculty of Medicine , Ilam University of Medical Sciences , Ilam , Iran
| | - Fereshteh Farajdokht
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences , Tabriz 51666-14756 , Iran
| | - Saiyad Bastaminejad
- Department of Biochemistry and Molecular Medicine, School of Medicine , Ilam University of Medical Sciences , Ilam , Iran
| | | | - Javad Mahmoudi
- Neurosciences Research Center (NSRC), Tabriz University of Medical Sciences , P.O. 51666-14756, Tabriz , Iran , e-mail:
| |
Collapse
|
|
30
|
Kim MJ, Jeon S, Burbulla LF, Krainc D. Acid ceramidase inhibition ameliorates α-synuclein accumulation upon loss of GBA1 function. Hum Mol Genet 2019; 27:1972-1988. [PMID: 29579237 DOI: 10.1093/hmg/ddy105] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 03/19/2018] [Indexed: 11/14/2022] Open
Abstract
GBA1 encodes the lysosomal enzyme β-glucocerebrosidase (GCase) which converts glucosylceramide into ceramide and glucose. Mutations in GBA1 lead to Gaucher's disease and are a major risk factor for Parkinson's disease (PD) and Dementia with Lewy bodies (DLB), synucleinopathies characterized by accumulation of intracellular α-synuclein. In this study, we examined whether decreased ceramide that is observed in GCase-deficient cells contributes to α-synuclein accumulation. We demonstrated that deficiency of GCase leads to a reduction of C18-ceramide species and altered intracellular localization of Rab8a, a small GTPase implicated in secretory autophagy, that contributed to impaired secretion of α-synuclein and accumulation of intracellular α-synuclein. This secretory defect was rescued by exogenous C18-ceramide or chemical inhibition of lysosomal enzyme acid ceramidase that converts lysosomal ceramide into sphingosine. Inhibition of acid ceramidase by carmofur resulted in increased ceramide levels and decreased glucosylsphingosine levels in GCase-deficient cells, and also reduced oxidized α-synuclein and levels of ubiquitinated proteins in GBA1-PD patient-derived dopaminergic neurons. Together, these results suggest that decreased ceramide generation via the catabolic lysosomal salvage pathway in GCase mutant cells contributes to α-synuclein accumulation, potentially due to impaired secretory autophagy. We thus propose that acid ceramidase inhibition which restores ceramide levels may be a potential therapeutic strategy to target synucleinopathies linked to GBA1 mutations including PD and DLB.
Collapse
Affiliation(s)
- Myung Jong Kim
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Sohee Jeon
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Lena F Burbulla
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Dimitri Krainc
- The Ken & Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| |
Collapse
|
|
31
|
Zaidi M, Yuen T, Sun L, Rosen CJ. Regulation of Skeletal Homeostasis. Endocr Rev 2018; 39:701-718. [PMID: 29897433 PMCID: PMC6173473 DOI: 10.1210/er.2018-00050] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 05/18/2018] [Indexed: 12/28/2022]
Abstract
Landmark advances in skeletal biology have arisen mainly from the identification of disease-causing mutations and the advent of rapid and selective gene-targeting technologies to phenocopy human disease in mice. Here, we discuss work on newly identified mechanisms controlling the remodeling of bone, communication of bone cells with cells of other lineages, and crosstalk between bone and vital organs as these relate to the therapeutic targeting of the skeleton.
Collapse
Affiliation(s)
- Mone Zaidi
- Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Tony Yuen
- Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Li Sun
- Mount Sinai Bone Program, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | | |
Collapse
|
|
32
|
Singh AK, Tripathi P, Cardell SL. Type II NKT Cells: An Elusive Population With Immunoregulatory Properties. Front Immunol 2018; 9:1969. [PMID: 30210505 PMCID: PMC6120993 DOI: 10.3389/fimmu.2018.01969] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Accepted: 08/10/2018] [Indexed: 12/20/2022] Open
Abstract
Natural killer T (NKT) cells are unique unconventional T cells that are reactive to lipid antigens presented on the non-polymorphic major histocompatibility class (MHC) I-like molecule CD1d. They have characteristics of both innate and adaptive immune cells, and have potent immunoregulatory roles in tumor immunity, autoimmunity, and infectious diseases. Based on their T cell receptor (TCR) expression, NKT cells are divided into two subsets, type I NKT cells with an invariant TCRα-chain (Vα24 in humans, Vα14 in mice) and type II NKT cells with diverse TCRs. While type I NKT cells are well-studied, knowledge about type II NKT cells is still limited, and it is to date only possible to identify subsets of this population. However, recent advances have shown that both type I and type II NKT cells play important roles in many inflammatory situations, and can sometimes regulate the functions of each other. Type II NKT cells can be both protective and pathogenic. Here, we review current knowledge on type II NKT cells and their functions in different disease settings and how these cells can influence immunological outcomes.
Collapse
Affiliation(s)
- Avadhesh Kumar Singh
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Prabhanshu Tripathi
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Susanna L Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| |
Collapse
|
|
33
|
Coexistence of Gaucher Disease and severe congenital neutropenia. Blood Cells Mol Dis 2018; 76:1-6. [PMID: 30473482 DOI: 10.1016/j.bcmd.2018.07.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Revised: 07/01/2018] [Accepted: 07/02/2018] [Indexed: 11/21/2022]
Abstract
Gaucher Disease (GD) is the most common lysosomal storage disorder has traditionally been classified into three clinical phenotypes. Type 3 GD is characterized by neurological involvement but neurological symptoms generally appear later in life than in type 2 disease. Neutropenia is much rarer than other hematological manifestations in GD and has not been scrutinized adequately. Severe congenital neutropenia (SCN) is a rare disease entity which is characterized by a paucity of peripherally circulating neutrophils with arrest of neutrophil maturation at the promyelocyte stage and consequent increased susceptibility to severe and recurrent infections. We report a patient who presented in the first year of life with visceral involvement and severe neutropenia in whom the propositus had a unique coexistence of Gaucher Disease and severe congenital neutropenia associated with a mutation in HAX1. In contrast to his expired siblings he had experienced no severe infections. These clinical observations suggest that enzyme replacement therapy may display a modulating factor with respect to the clinical course of SCN. SYNOPSIS: Our patient is the only report of the combination of Gaucher Disease and Kostmann Syndrome in the literature. The clinical course of our patient is not severe when comparing with exitus siblings and other Kostmann Syndrome patients. But when considering the patient's only clinical difference is ERT, this case is very important to emphasise the role of enzyme replacement therapy in bone marrow.
Collapse
|
|
34
|
Pandey MK, Grabowski GA, Köhl J. An unexpected player in Gaucher disease: The multiple roles of complement in disease development. Semin Immunol 2018; 37:30-42. [PMID: 29478824 DOI: 10.1016/j.smim.2018.02.006] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/15/2018] [Accepted: 02/16/2018] [Indexed: 12/14/2022]
Abstract
The complement system is well appreciated for its role as an important effector of innate immunity that is activated by the classical, lectin or alternative pathway. C5a is one important mediator of the system that is generated in response to canonical and non-canonical C5 cleavage by circulating or cell-derived proteases. In addition to its function as a chemoattractant for neutrophils and other myeloid effectors, C5a and its sister molecule C3a have concerted roles in cell homeostasis and surveillance. Through activation of their cognate G protein coupled receptors, C3a and C5a regulate multiple intracellular pathways within the mitochondria and the lysosomal compartments that harbor multiple enzymes critical for protein, carbohydrate and lipid metabolism. Genetic mutations of such lysosomal enzymes or their receptors can result in the compartmental accumulation of specific classes of substrates in this organelle summarized as lysosomal storage diseases (LSD). A frequent LSD is Gaucher disease (GD), caused by autosomal recessively inherited mutations in GBA1, resulting in functional defects of the encoded enzyme, acid β-glucosidase (glucocerebrosidase, GCase). Such mutations promote excessive accumulation of β-glucosylceramide (GC or GL1) in innate and adaptive immune cells frequently associated with chronic inflammation. Recently, we uncovered an unexpected link between the C5a and C5a receptor 1 (C5aR1) axis and the accumulation of GL1 in experimental and clinical GD. Here, we will review the pathways of complement activation in GD, its role as a mediator of the inflammatory response, and its impact on glucosphingolipid metabolism. Further, we will discuss the potential role of the C5a/C5aR1 axis in GL1-specific autoantibody formation and as a novel therapeutic target in GD.
Collapse
Affiliation(s)
- Manoj K Pandey
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; The Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.
| | - Gregory A Grabowski
- Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; The Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA
| | - Jörg Köhl
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA; The Department of Pediatrics of the University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA; Institute for Systemic Inflammation Research, University of Lübeck, 23562, Lübeck, Germany.
| |
Collapse
|
|
35
|
Kato S, Berzofsky JA, Terabe M. Possible Therapeutic Application of Targeting Type II Natural Killer T Cell-Mediated Suppression of Tumor Immunity. Front Immunol 2018; 9:314. [PMID: 29520281 PMCID: PMC5827362 DOI: 10.3389/fimmu.2018.00314] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Accepted: 02/05/2018] [Indexed: 12/17/2022] Open
Abstract
Natural killer T (NKT) cells are a unique T cell subset that exhibits characteristics from both the innate immune cells and T cells. There are at least two subsets of NKT cells, type I and type II. These two subsets of NKT cells have opposite functions in antitumor immunity. Type I NKT cells usually enhance and type II NKT cells suppress antitumor immunity. In addition, these two subsets of NKT cells cross-regulate each other. In this review, we mainly focus on immunosuppressive NKT cells, type II NKT cells. After summarizing their definition, experimental tools to study them, and subsets of them, we will discuss possible therapeutic applications of type II NKT cell pathway targeted therapies.
Collapse
Affiliation(s)
- Shingo Kato
- Department of Gastroenterology and Hepatology, Yokohama City University School of Medicine, Yokohama, Japan
| | - Jay A. Berzofsky
- Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Masaki Terabe
- Molecular Immunogenetics and Vaccine Research Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| |
Collapse
|
|
36
|
Rup B, Alon S, Amit-Cohen BC, Brill Almon E, Chertkoff R, Tekoah Y, Rudd PM. Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems-The taliglucerase alfa story. PLoS One 2017; 12:e0186211. [PMID: 29088235 PMCID: PMC5663370 DOI: 10.1371/journal.pone.0186211] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 08/01/2017] [Indexed: 01/28/2023] Open
Abstract
Plants are a promising alternative for the production of biotherapeutics. Manufacturing in-planta adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies.
Collapse
Affiliation(s)
- Bonita Rup
- Bonnie Rup Consulting, LLC, Reading, Massachusetts, United States of America
| | - Sari Alon
- Product Development, Protalix LTD, Carmiel, Israel
| | | | | | | | - Yoram Tekoah
- Research and Development, Protalix LTD, Carmiel, Israel
- * E-mail:
| | - Pauline M. Rudd
- National Institute for Bioprocessing Research and Training, Dublin, Ireland
- Bioprocessing Technology Institute, AStar, Singapore
| |
Collapse
|
|
37
|
Beaton B, Monzón JLS, Hughes DA, Pastores GM. Gaucher disease: risk stratification and comorbidities. Expert Opin Orphan Drugs 2017. [DOI: 10.1080/21678707.2017.1385455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Brendan Beaton
- Lysosomal Storage Disorder Unit, Royal Free NHS FT and University College London, London, UK
| | | | - Derralynn A. Hughes
- Lysosomal Storage Disorder Unit, Royal Free NHS FT and University College London, London, UK
- Department of Haematology and Palliative Care, Royal Free NHS FT, University College London, London, UK
| | - Gregory M. Pastores
- Department of Medicine/National Centre for Inherited Metabolic Disorders, Mater Misericordiae University Hospital and University College Dublin, Dublin, Ireland
| |
Collapse
|
|
38
|
Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems. Physiol Rev 2017; 97:1295-1349. [DOI: 10.1152/physrev.00036.2016] [Citation(s) in RCA: 241] [Impact Index Per Article: 30.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 03/29/2017] [Accepted: 04/04/2017] [Indexed: 12/13/2022] Open
Abstract
The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.
Collapse
Affiliation(s)
- Kazuo Okamoto
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Tomoki Nakashima
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Masahiro Shinohara
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Takako Negishi-Koga
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Noriko Komatsu
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Asuka Terashima
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Shinichiro Sawa
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Takeshi Nitta
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| | - Hiroshi Takayanagi
- Department of Osteoimmunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan; Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo, Japan; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology (AMED-CREST), Tokyo, Japan
| |
Collapse
|
|
39
|
Abstract
Lysosomes are cytoplasmic organelles that contain a variety of different hydrolases. A genetic deficiency in the enzymatic activity of one of these hydrolases will lead to the accumulation of the material meant for lysosomal degradation. Examples include glycogen in the case of Pompe disease, glycosaminoglycans in the case of the mucopolysaccharidoses, glycoproteins in the cases of the oligosaccharidoses, and sphingolipids in the cases of Niemann-Pick disease types A and B, Gaucher disease, Tay-Sachs disease, Krabbe disease, and metachromatic leukodystrophy. Sometimes, the lysosomal storage can be caused not by the enzymatic deficiency of one of the hydrolases, but by the deficiency of an activator protein, as occurs in the AB variant of GM2 gangliosidosis. Still other times, the accumulated lysosomal material results from failed egress of a small molecule as a consequence of a deficient transporter, as in cystinosis or Salla disease. In the last couple of decades, enzyme replacement therapy has become available for a number of lysosomal storage diseases. Examples include imiglucerase, taliglucerase and velaglucerase for Gaucher disease, laronidase for Hurler disease, idursulfase for Hunter disease, elosulfase for Morquio disease, galsulfase for Maroteaux-Lamy disease, alglucosidase alfa for Pompe disease, and agalsidase alfa and beta for Fabry disease. In addition, substrate reduction therapy has been approved for certain disorders, such as eliglustat for Gaucher disease. The advent of treatment options for some of these disorders has led to newborn screening pilot studies, and ultimately to the addition of Pompe disease and Hurler disease to the Recommended Uniform Screening Panel (RUSP) in 2015 and 2016, respectively.
Collapse
Affiliation(s)
- Carlos R. Ferreira
- Division of Genetics and Metabolism, Children’s National Health System, Washington, DC, USA
- George Washington University School of Medicine & Health Sciences, Washington, DC, USA
- Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| | - William A. Gahl
- Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
40
|
Abstract
Lysosomal storage disorders (LSDs) are infrequent to rare conditions caused by mutations that lead to a disruption in the usual sequential degradation of macromolecules or their transit within the cell. Gaucher disease (GD), a lipidosis, is among the most common LSD, with an estimated incidence of 1 in 40,000 among the Caucasian, non-Jewish population. Studies have indicated an increased frequency of polyclonal and monoclonal gammopathy among patients with GD. It has been shown that two major sphingolipids that accumulate in GD, namely, β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Investigations undertaken in an affected mouse model revealed βGL1-22- and LGL1-specific NKT cells were present and constitutively promoted the expression of a T-follicular helper (TFH) phenotype; injection of these lipids led to downstream induction of germinal center B cells, hypergammaglobulinemia, and the production of antilipid antibodies. Subsequent studies have found clonal immunoglobulin in 33% of sporadic human monoclonal gammopathies is also specific for the lysolipids LGL1 and lysophosphatidylcholine (LPC). Furthermore, substrate reduction ameliorated GD-associated gammopathy in mice. It had been hypothesized that chronic antigenic stimulation by the abnormal lipid storage and associated immune dysregulation may be the underlying mechanism for the increased incidence of monoclonal and polyclonal gammopathies, as well as an increased incidence of multiple myeloma in patients with GD. Current observations support this proposition and illustrate the value of investigations into rare diseases, which as 'experiments of nature' may provide insights into conditions found in the general population that continue to remain incompletely understood.
Collapse
|
|
41
|
de la Mata M, Cotán D, Oropesa-Ávila M, Villanueva-Paz M, de Lavera I, Álvarez-Córdoba M, Luzón-Hidalgo R, Suárez-Rivero JM, Tiscornia G, Sánchez-Alcázar JA. Coenzyme Q 10 partially restores pathological alterations in a macrophage model of Gaucher disease. Orphanet J Rare Dis 2017; 12:23. [PMID: 28166796 PMCID: PMC5292786 DOI: 10.1186/s13023-017-0574-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Accepted: 01/20/2017] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease. In addition, the beneficial effects of coenzyme Q10 (CoQ) supplementation on cellular alterations were evaluated. Chemically-induced Gaucher macrophages were developed by differentiateing THP-1 monocytes to macrophages by treatment with phorbol 12-myristate 13-acetate (PMA) and then inhibiting intracellular GCase with conduritol B-epoxide (CBE), a specific irreversible inhibitor of GCase activity, and supplementing the medium with exogenous GlcCer. This cell model accumulated up to 16-fold more GlcCer compared with control THP-1 cells. RESULTS Chemically-induced Gaucher macrophages showed impaired autophagy flux associated with mitochondrial dysfunction and increased oxidative stress, inflammasome activation and impaired efferocytosis. All abnormalities were partially restored by supplementation with CoQ. CONCLUSION These data suggest that targeting mitochondria function and oxidative stress by CoQ can ameliorate the pathological phenotype of Gaucher cells. Chemically-induced Gaucher macrophages provide cellular models that can be used to investigate disease pathogenesis and explore new therapeutics for GD.
Collapse
Affiliation(s)
- Mario de la Mata
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - David Cotán
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Manuel Oropesa-Ávila
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Marina Villanueva-Paz
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Isabel de Lavera
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Mónica Álvarez-Córdoba
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Raquel Luzón-Hidalgo
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Juan M Suárez-Rivero
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain.,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Gustavo Tiscornia
- Department of Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
| | - José A Sánchez-Alcázar
- Centro Andaluz de Biología del Desarrollo (CABD), Consejo Superior de Investigaciones Científicas, Universidad Pablo de Olavide, Carretera de Utrera Km 1, Sevilla, 41013, Spain. .,Centro de Investigación Biomédica en Red: Enfermedades Raras, Instituto de Salud Carlos III, Madrid, 28029, Spain.
| |
Collapse
|
|
42
|
Mistry PK, Lopez G, Schiffmann R, Barton NW, Weinreb NJ, Sidransky E. Gaucher disease: Progress and ongoing challenges. Mol Genet Metab 2017; 120:8-21. [PMID: 27916601 PMCID: PMC5425955 DOI: 10.1016/j.ymgme.2016.11.006] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 11/15/2016] [Accepted: 11/16/2016] [Indexed: 12/31/2022]
Abstract
Over the past decades, tremendous progress has been made in the field of Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Many of the colossal achievements took place during the course of the sixty-year tenure of Dr. Roscoe Brady at the National Institutes of Health. These include the recognition of the enzymatic defect involved, the isolation and characterization of the protein, the localization and characterization of the gene and its nearby pseudogene, as well as the identification of the first mutant alleles in patients. The first treatment for Gaucher disease, enzyme replacement therapy, was conceived of, developed and tested at the Clinical Center of the National Institutes of Health. Advances including recombinant production of the enzyme, the development of mouse models, pioneering gene therapy experiments, high throughput screens of small molecules and the generation of induced pluripotent stem cell models have all helped to catapult research in Gaucher disease into the twenty-first century. The appreciation that mutations in the glucocerebrosidase gene are an important risk factor for parkinsonism further expands the impact of this work. However, major challenges still remain, some of which are described here, that will provide opportunities, excitement and discovery for the next generations of Gaucher investigators.
Collapse
Affiliation(s)
- Pramod K Mistry
- Yale University School of Medicine, Department of Internal Medicine, 333 Cedar Street, LMP 1080, P.O. Box 208019, New Haven, CT 06520-8019, United States.
| | - Grisel Lopez
- Medical Genetics Branch, NHGRI, NIH, Bldg 35A Room 1E623, 35 Convent Drive, Bethesda, MD 20892, United States.
| | - Raphael Schiffmann
- Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX 75226, United States.
| | - Norman W Barton
- Therapeutic Area Head Neuroscience, Shire plc, 300 Shire Way, Lexington, MA 02421, United States.
| | - Neal J Weinreb
- University of Miami Miller School of Medicine, Department of Human Genetics and Medicine (Hematology), UHealth Sylvester Coral Springs, 8170 Royal Palm Boulevard, Coral Springs, FL 33065, United States.
| | - Ellen Sidransky
- Medical Genetics Branch, NHGRI, NIH, Bldg 35A Room 1E623, 35 Convent Drive, Bethesda, MD 20892, United States.
| |
Collapse
|
|
43
|
Validating glycoprotein non-metastatic melanoma B (gpNMB, osteoactivin), a new biomarker of Gaucher disease. Blood Cells Mol Dis 2016; 68:47-53. [PMID: 28003098 DOI: 10.1016/j.bcmd.2016.12.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/11/2016] [Accepted: 12/12/2016] [Indexed: 11/23/2022]
Abstract
In the spleens of Gaucher disease mice and patients, there is a striking elevation of expression of glycoprotein non-Metastatic Melanoma B (gpNMB). We conducted a study in a large cohort of patients with Gaucher disease to assess the utility of serum levels of soluble fragment of gpNMB as a biomarker of disease activity. There was >15-fold elevation of gpNMB in sera of untreated patients with Gaucher disease. gpNMB levels correlated with overall disease severity as well as the severity of individual organ compartments: liver, spleen, bone and hematological disease. Imiglucerase enzyme replacement therapy resulted in significant reduction of gpNMB. Serum levels of gpNMB were highly correlated with accumulation of bioactive lipid substrate of Gaucher disease, glucosylsphingosine as well as established biomarkers, chitotriosidase and chemokine, CCL18. Our results suggest utility of gpNMB as a biomarker of Gaucher disease to monitor individual patients and cohorts of patients for disease progression or response to therapy. Investigation of gpNMB in Gaucher disease pathophysiology is likely to illuminate our understanding disease mechanisms.
Collapse
|
|
44
|
Reihani N, Arlet JB, Dussiot M, de Villemeur TB, Belmatoug N, Rose C, Colin-Aronovicz Y, Hermine O, Le Van Kim C, Franco M. Unexpected macrophage-independent dyserythropoiesis in Gaucher disease. Haematologica 2016; 101:1489-1498. [PMID: 27470603 DOI: 10.3324/haematol.2016.147546] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 07/26/2016] [Indexed: 01/08/2023] Open
Abstract
Gaucher disease is a rare inherited disease caused by a deficiency in glucocerebrosidase leading to lipid accumulation in cells of mononuclear-macrophage lineage known as Gaucher cells. Visceral enlargement, bone involvement, mild anemia and thrombocytopenia are the major manifestations of Gaucher disease. We have previously demonstrated that the red blood cells from patients exhibit abnormal properties, which indicates a new role in Gaucher disease pathophysiology. To investigate whether erythroid progenitors are affected, we examined the in vitro erythropoiesis from the peripheral CD34+ cells of patients and controls. CD34- cells were differentiated into macrophages and co-cultivated with erythroblasts. We showed an accelerated differentiation of erythroid progenitors without maturation arrest from patients compared to controls. This abnormal differentiation persisted in the patients when the same experiments were performed without macrophages, which strongly suggested that dyserythropoiesis in Gaucher disease is secondary to an inherent defect in the erythroid progenitors. The accelerated differentiation was associated with reduced cell proliferation. As a result, less mature erythroid cells were generated in vitro in the Gaucher disease cultures compared to the control. We then compared the biological characteristics of untreated patients according to their anemic status. Compared to the non-anemic group, the anemic patients exhibit higher plasma levels of growth differentiation factor-15, a marker of ineffective erythropoiesis, but they had no indicators of hemolysis and similar reticulocyte counts. Taken together, these results demonstrated an unsuspected dyserythropoiesis that was independent of the macrophages and could participate, at least in part, to the basis of anemia in Gaucher disease.
Collapse
Affiliation(s)
- Nelly Reihani
- Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris
| | - Jean-Benoit Arlet
- Sorbonne Paris-Cité, Université Paris Descartes, Service de Médecine Interne, Assistance publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Inserm UMR 1163, CNRS ERL 8254, Hôpital Necker, Institut Imagine, Laboratoire d'excellence GR-Ex, Paris
| | - Michael Dussiot
- Sorbonne Paris-Cité, Université Paris Descartes, Inserm UMR 1163, CNRS ERL 8254, Institut Imagine, Hôpital Necker, Laboratoire d'excellence GR-Ex, Paris
| | - Thierry Billette de Villemeur
- Sorbonne Université, Université Pierre et Marie Curie, Service de Neuropédiatrie Hôpital Trousseau, Assistance publique-Hôpitaux de Paris, Hôpital et GRC ConCer-LD, Paris
| | - Nadia Belmatoug
- Hôpitaux universitaires Paris Nord Val de Seine, Assistance publique-Hôpitaux de Paris, Hôpital Beaujon, Service de Médecine Interne, Centre de Référence des Maladies Lysosomales, Clichy, France
| | - Christian Rose
- Université Catholique de Lille, Hôpital Saint Vincent de Paul, Service d'Hématologie, Lille, France
| | - Yves Colin-Aronovicz
- Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris
| | - Olivier Hermine
- Sorbonne Paris-Cité, Université Paris Descartes, Assistance publique-Hôpitaux de Paris, Hôpital Necker, Service d'Hématologie, Inserm UMR 1163, CNRS ERL 8254, Institut Imagine, Laboratoire d'excellence GR-Ex, Paris, Inserm UMR 1163, CNRS, France
| | - Caroline Le Van Kim
- Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris
| | - Melanie Franco
- Université Sorbonne Paris Cité, Université Paris Diderot, Inserm, INTS, Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, Paris
| |
Collapse
|
|
45
|
Hersrud SL, Kovács AD, Pearce DA. Antigen presenting cell abnormalities in the Cln3(-/-) mouse model of juvenile neuronal ceroid lipofuscinosis. BIOCHIMICA ET BIOPHYSICA ACTA 2016; 1862:1324-36. [PMID: 27101989 PMCID: PMC4899816 DOI: 10.1016/j.bbadis.2016.04.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/10/2016] [Accepted: 04/11/2016] [Indexed: 10/21/2022]
Abstract
Mutations of the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive lysosomal storage disorder that causes progressive neurodegeneration in children and adolescents. There is evidence of immune system involvement in pathology that has been only minimally investigated. We characterized bone marrow stem cell-derived antigen presenting cells (APCs), peritoneal macrophages, and leukocytes from spleen and blood, harvested from the Cln3(-/-) mouse model of JNCL. We detected dramatically elevated CD11c surface levels and increased total CD11c protein in Cln3(-/-) cell samples compared to wild type. This phenotype was specific to APCs and also to a loss of CLN3, as surface levels did not differ from wild type in other leukocyte subtypes nor in cells from two other NCL mouse models. Subcellularly, CD11c was localized to lipid rafts, indicating that perturbation of surface levels is attributable to derangement of raft dynamics, which has previously been shown in Cln3 mutant cells. Interrogation of APC function revealed that Cln3(-/-) cells have increased adhesiveness to CD11c ligands as well as an abnormal secretory pattern that closely mimics what has been previously reported for Cln3 mutant microglia. Our results show that CLN3 deficiency alters APCs, which can be a major contributor to the autoimmune response in JNCL.
Collapse
Affiliation(s)
- Samantha L Hersrud
- Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, United States; Sanford School of Medicine, University of South Dakota, Vermillion, SD 57105, United States
| | - Attila D Kovács
- Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, United States; Sanford School of Medicine, University of South Dakota, Vermillion, SD 57105, United States
| | - David A Pearce
- Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, United States; Sanford School of Medicine, University of South Dakota, Vermillion, SD 57105, United States.
| |
Collapse
|
|
46
|
Astudillo L, Therville N, Colacios C, Ségui B, Andrieu-Abadie N, Levade T. Glucosylceramidases and malignancies in mammals. Biochimie 2016; 125:267-80. [DOI: 10.1016/j.biochi.2015.11.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 11/09/2015] [Indexed: 01/11/2023]
|
|
47
|
Iqbal J, Yuen T, Sun L, Zaidi M. From the gut to the strut: where inflammation reigns, bone abstains. J Clin Invest 2016; 126:2045-8. [PMID: 27111233 DOI: 10.1172/jci87430] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
In this issue of the JCI, Li et al. show that germ-free mice, when chemically castrated, do not lose bone - a finding that unequivocally establishes a role of gut microbiota in mediating hypogonadal bone loss. Additionally and not unexpectedly, probiotics reversed hypogonadal osteopenia in sex steroid-deficient mice by preventing the disruption of gut barrier function and dampening cytokine-induced inflammation. The authors propose that TNFα is a key mediator; however, it is very likely that other molecules - including IL-1, IL-6, IL-17, RANKL, OPG, and CCL2 - modulate probiotic action. The results of this study highlight the potential for repurposing probiotics for the therapy of osteoporosis. Future placebo-controlled clinical trials will be required to establish safety and efficacy of probiotics in reducing fracture risk in people.
Collapse
|
|
48
|
Vargiami E, Dimitriadou M, Economou M, Christoforidis A, Zafeiriou DI. Long-term response in biochemical markers of bone turnover during enzyme replacement therapy in a case-series of patients with Gaucher disease type I from Northern Greece. Hippokratia 2016; 20:153-159. [PMID: 28416913 PMCID: PMC5388517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
BACKGROUND Gaucher disease (GD) is a lysosomal storage disorder characterized by severe skeletal complications. Bone complications are an important cause of morbidity of GD and are thought to result from imbalance in bone remodeling. The objective of this case series was to analyze the long-term effect of enzyme replacement therapy on chemokines MIP-1a and MIP-1b, cytokines IL-3, IL-6, IL-10, and IL-12, osteoprotegerin (OPG) and osteocalcin (BGP), chitotriosidase, quantitative ultrasound sonography (QUS), bone magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) in patients with GD in Northern Greece. In addition, the study aimed in investigating possible relationship between the above mentioned parameters. PATIENTS AND METHODS Seven patients with GD type I (three males and four females) were included in the study. Mean age was 26.29 ± 15.34 years (range 7-47 years). Six patients were receiving enzyme replacement therapy (ERT), with 40-60 IU/kg of imiglucerase weekly, for a mean period of 36 months prior to study initiation. One patient started ERT after his inclusion in the study. The levels of MIP-1a, MIP-1b, IL-3, IL-6, IL-10, IL-12, OPG, BGP, chitotriosidase, bone imaging parameters assessed with two different techniques (QUS and DXA) and MRI data were estimated at baseline (T0) and after two years on ERT. RESULTS Chitotriosidase, MIP-1a, and IL-6 levels decreased in all patients after two years of ERT (p =0.05). In contrast, OPG and BGP levels increased (p =0.04 and p =0.02, respectively). Bone mineral density (BMD) demonstrated a progressive improvement with regards to the Z-score in all patients (p =0.05). The decrease in the plasma levels of MIP-1a strongly correlated with a decrease in the plasma levels of chitotriosidase. Additionally, decreased plasma levels of IL-6 were correlated with increased Z-score both at baseline (T0) as well as two years later, in all patients. There was no correlation between MRI findings and any inflammatory biomarker. CONCLUSIONS Measurement of serum markers in patients with GD under ERT could be used as an auxiliary tool in the monitoring of bone involvement, in combination with MRI imaging and BMD. However, larger studies involving higher numbers of GD patients are needed to confirm these conclusions. Hippokratia 2016, 20(2): 153-159.
Collapse
Affiliation(s)
- E Vargiami
- 1 Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| | - M Dimitriadou
- 1 Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| | - M Economou
- 1 Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| | - A Christoforidis
- 1 Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| | - D I Zafeiriou
- 1 Department of Pediatrics, Hippokratio General Hospital, Aristotle University, Thessaloniki, Greece
| |
Collapse
|
|
49
|
Koppe T, Doneda D, Siebert M, Paskulin L, Camargo M, Tirelli KM, Vairo F, Daudt L, Schwartz IVD. The prognostic value of the serum ferritin in a southern Brazilian cohort of patients with Gaucher disease. Genet Mol Biol 2016; 39:30-4. [PMID: 27007895 PMCID: PMC4807389 DOI: 10.1590/1678-4685-gmb-2015-0125] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2015] [Accepted: 09/28/2015] [Indexed: 01/17/2023] Open
Abstract
The clinical utility of serum ferritin as a biomarker of disease severity and prognosis in Gaucher disease (GD) is still debated. Here, we aimed to evaluate ferritin and its relation to clinicolaboratory parameters of GD patients seen at the Reference Center for Gaucher Disease of Rio Grande do Sul, Brazil, so as to gather evidence on the utility of ferritin as a biomarker of this condition. A retrospective chart review was performed collecting pre-and posttreatment data from GD patients. Eighteen patients with ferritin levels available before and after treatment were included in the study. Nine of these participants were males, and seventeen had type I GD. All patients were given either enzyme replacement (n = 16) or substrate reduction therapy (n = 2), and ferritin was found to decrease from 756 [318-1441] ng/mL at baseline to 521 [227-626] ng/mL (p=0.025) after 28.8 month soft treatment. Serum ferritin levels did not correlate with measures of disease severity, but showed an association with age at onset of treatment (ρ= 0.880; n = 18; p < 0.001). In conclusion, although serum ferritin did not correlate with disease severity, after a median 28.8 months of treatment, clinical outcomes had clearly improved, and ferritin levels had decreased.
Collapse
Affiliation(s)
- Tiago Koppe
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Divair Doneda
- Laboratório de Técnica Dietética, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Marina Siebert
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Livia Paskulin
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Matheus Camargo
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | | | - Filippo Vairo
- Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brazil
| | - Liane Daudt
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Ida Vanessa D Schwartz
- Departamento de Genética, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| |
Collapse
|
|
50
|
Panicker LM, Miller D, Awad O, Bose V, Lun Y, Park TS, Zambidis ET, Sgambato JA, Feldman RA. Gaucher iPSC-derived macrophages produce elevated levels of inflammatory mediators and serve as a new platform for therapeutic development. Stem Cells 2015; 32:2338-49. [PMID: 24801745 DOI: 10.1002/stem.1732] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2013] [Accepted: 04/09/2014] [Indexed: 12/21/2022]
Abstract
Gaucher disease (GD) is an autosomal recessive disorder caused by mutations in the acid β-glucocerebrosidase (GCase; GBA) gene. The hallmark of GD is the presence of lipid-laden Gaucher macrophages, which infiltrate bone marrow and other organs. These pathological macrophages are believed to be the sources of elevated levels of inflammatory mediators present in the serum of GD patients. The alteration in the immune environment caused by GD is believed to play a role in the increased risk of developing multiple myeloma and other malignancies in GD patients. To determine directly whether Gaucher macrophages are abnormally activated and whether their functional defects can be reversed by pharmacological intervention, we generated GD macrophages by directed differentiation of human induced pluripotent stem cells (hiPSC) derived from patients with types 1, 2, and 3 GD. GD hiPSC-derived macrophages expressed higher levels of tumor necrosis factor α, IL-6, and IL-1β than control cells, and this phenotype was exacerbated by treatment with lipopolysaccharide. In addition, GD hiPSC macrophages exhibited a striking delay in clearance of phagocytosed red blood cells, recapitulating the presence of red blood cell remnants in Gaucher macrophages from bone marrow aspirates. Incubation of GD hiPSC macrophages with recombinant GCase, or with the chaperones isofagomine and ambroxol, corrected the abnormal phenotypes of GD macrophages to an extent that reflected their known clinical efficacies. We conclude that Gaucher macrophages are the likely source of the elevated levels of inflammatory mediators in the serum of GD patients and that GD hiPSC are valuable new tools for studying disease mechanisms and drug discovery.
Collapse
Affiliation(s)
- Leelamma M Panicker
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | | | | | | | | | | | | | | | | |
Collapse
|