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Wang XQ, Chen CB, Zhao WJ, Fu GB, Zhai Y. Rare adult neuronal ceroid lipofuscinosis associated with CLN6 gene mutations: A case report. World J Clin Cases 2023; 11:3533-3541. [PMID: 37383919 PMCID: PMC10294197 DOI: 10.12998/wjcc.v11.i15.3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/06/2023] [Accepted: 04/13/2023] [Indexed: 05/25/2023] Open
Abstract
BACKGROUND Adult neuronal ceroid lipofuscinosis (ANCL) can be caused by compound heterozygous recessive mutations in CLN6. The main clinical features of the disease are neurodegeneration, progressive motor dysfunction, seizures, cognitive decline, ataxia, vision loss and premature death.
CASE SUMMARY A 37-year-old female presented to our clinic with a 3-year history of limb weakness and gradually experiencing unstable walking. The patient was diagnosed with CLN6 type ANCL after the identification of mutations in the CLN6 gene. The patient was treated with antiepileptic drugs. The patient is under ongoing follow-up. Unfortunately, the patient’s condition has deteriorated, and she is currently unable to care for herself.
CONCLUSION There is presently no effective treatment for ANCL. However, early diagnosis and symptomatic treatment are possible.
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Affiliation(s)
- Xue-Qiang Wang
- Department of Neurology, Sanya People’s Hospital, West China (Sanya) Hospital, Sichuan University, Sanya 572000, Hainan Province, China
| | - Chuan-Bi Chen
- Department of Pediatrics, Sanya Women and Children’s Hospital Managed by Shanghai Children's Medical Center, Sanya 572000, Hainan Province, China
| | - Wen-Jie Zhao
- Department of Neurology, The First Affiliated Hospital of Hainan Medical College, Haikou 570100, Hainan Province, China
| | - Guang-Bin Fu
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
| | - Yu Zhai
- Department of Neurology, Hainan Western Central Hospital, Danzhou 571799, Hainan Province, China
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Swier VJ, White KA, Johnson TB, Sieren JC, Johnson HJ, Knoernschild K, Wang X, Rohret FA, Rogers CS, Pearce DA, Brudvig JJ, Weimer JM. A Novel Porcine Model of CLN2 Batten Disease that Recapitulates Patient Phenotypes. Neurotherapeutics 2022; 19:1905-1919. [PMID: 36100791 PMCID: PMC9723024 DOI: 10.1007/s13311-022-01296-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2022] [Indexed: 12/13/2022] Open
Abstract
CLN2 Batten disease is a lysosomal disorder in which pathogenic variants in CLN2 lead to reduced activity in the enzyme tripeptidyl peptidase 1. The disease typically manifests around 2 to 4 years of age with developmental delay, ataxia, seizures, inability to speak and walk, and fatality between 6 and 12 years of age. Multiple Cln2 mouse models exist to better understand the etiology of the disease; however, these models are unable to adequately recapitulate the disease due to differences in anatomy and physiology, limiting their utility for therapeutic testing. Here, we describe a new CLN2R208X/R208X porcine model of CLN2 disease. We present comprehensive characterization showing behavioral, pathological, and visual phenotypes that recapitulate those seen in CLN2 patients. CLN2R208X/R208X miniswine present with gait abnormalities at 6 months of age, ERG waveform declines at 6-9 months, vision loss at 11 months, cognitive declines at 12 months, seizures by 15 months, and early death at 18 months due to failure to thrive. CLN2R208X/R208X miniswine also showed classic storage material accumulation and glial activation in the brain at 6 months, and cortical atrophy at 12 months. Thus, the CLN2R208X/R208X miniswine model is a valuable resource for biomarker discovery and therapeutic development in CLN2 disease.
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Affiliation(s)
- Vicki J Swier
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Katherine A White
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Jessica C Sieren
- Department of Radiology, University of Iowa, Iowa City, IA, USA
- Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA
| | - Hans J Johnson
- Department of Electrical and Computer Engineering, University of Iowa, Iowa City, IA, USA
| | - Kevin Knoernschild
- Department of Radiology, University of Iowa, Iowa City, IA, USA
- Department of Biomedical Engineering, University of Iowa, Iowa City, IA, USA
| | | | | | | | - David A Pearce
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
| | - Jon J Brudvig
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA
| | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
- Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
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Mondal A, Appu AP, Sadhukhan T, Bagh MB, Previde RM, Sadhukhan S, Stojilkovic S, Liu A, Mukherjee AB. Ppt1-deficiency dysregulates lysosomal Ca ++ homeostasis contributing to pathogenesis in a mouse model of CLN1 disease. J Inherit Metab Dis 2022; 45:635-656. [PMID: 35150145 PMCID: PMC9090967 DOI: 10.1002/jimd.12485] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 11/08/2022]
Abstract
Inactivating mutations in the PPT1 gene encoding palmitoyl-protein thioesterase-1 (PPT1) underlie the CLN1 disease, a devastating neurodegenerative lysosomal storage disorder. The mechanism of pathogenesis underlying CLN1 disease has remained elusive. PPT1 is a lysosomal enzyme, which catalyzes the removal of palmitate from S-palmitoylated proteins (constituents of ceroid lipofuscin) facilitating their degradation and clearance by lysosomal hydrolases. Thus, it has been proposed that Ppt1-deficiency leads to lysosomal accumulation of ceroid lipofuscin leading to CLN1 disease. While S-palmitoylation is catalyzed by palmitoyl acyltransferases (called ZDHHCs), palmitoyl-protein thioesterases (PPTs) depalmitoylate these proteins. We sought to determine the mechanism by which Ppt1-deficiency may impair lysosomal degradative function leading to infantile neuronal ceroid lipofuscinosis pathogenesis. Here, we report that in Ppt1-/- mice, which mimic CLN1 disease, low level of inositol 3-phosphate receptor-1 (IP3R1) that mediates Ca++ transport from the endoplasmic reticulum to the lysosome dysregulated lysosomal Ca++ homeostasis. Intriguingly, the transcription factor nuclear factor of activated T-cells, cytoplasmic 4 (NFATC4), which regulates IP3R1-expression, required S-palmitoylation for trafficking from the cytoplasm to the nucleus. We identified two palmitoyl acyltransferases, ZDHHC4 and ZDHHC8, which catalyzed S-palmitoylation of NFATC4. Notably, in Ppt1-/- mice, reduced ZDHHC4 and ZDHHC8 levels markedly lowered S-palmitoylated NFATC4 (active) in the nucleus, which inhibited IP3R1-expression, thereby dysregulating lysosomal Ca++ homeostasis. Consequently, Ca++ -dependent lysosomal enzyme activities were markedly suppressed. Impaired lysosomal degradative function impaired autophagy, which caused lysosomal storage of undigested cargo. Importantly, IP3R1-overexpression in Ppt1-/- mouse fibroblasts ameliorated this defect. Our results reveal a previously unrecognized role of Ppt1 in regulating lysosomal Ca++ homeostasis and suggest that this defect contributes to pathogenesis of CLN1 disease.
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Affiliation(s)
- Avisek Mondal
- Section on Developmental Genetics, Division of Translational Medicine
| | - Abhilash P. Appu
- Section on Developmental Genetics, Division of Translational Medicine
| | - Tamal Sadhukhan
- Section on Developmental Genetics, Division of Translational Medicine
| | - Maria B. Bagh
- Section on Developmental Genetics, Division of Translational Medicine
| | - Rafael M. Previde
- Section on Cellular Signaling, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830
| | | | - Stanko Stojilkovic
- Section on Cellular Signaling, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830
| | - Aiyi Liu
- Biostatistics and Bioinformatics Branch, Division of Intramural Population Health Research, Eunice Kennedy-Shriver National Institute of Child Health and Human Development, The National Institutes of Health, Bethesda, Maryland 20892-1830
| | - Anil B Mukherjee
- Section on Developmental Genetics, Division of Translational Medicine
- Correspondence to AM () or ABM ()
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Qiao Y, Gu Y, Cheng Y, Su Y, Lv N, Shang Q, Xing Q. Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7. Front Genet 2022; 13:807515. [PMID: 35154277 PMCID: PMC8826235 DOI: 10.3389/fgene.2022.807515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 01/06/2022] [Indexed: 11/24/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are among the most common progressive encephalopathies of childhood. Neuronal ceroid lipofuscinosis 7 (CLN7), one of the late infantile-onset NCLs, is an autosomal recessive disorder caused by mutations in the MFSD8 gene on chromosome 4q28. Almost all reported mutations of MFSD8 in CLN7 patients were SNVs. However, we report a 4-year-old boy with CLN7 harboring compound heterozygous mutations in the MFSD8 gene, including one novel two-nucleotide deletion c.136_137delAT (p. M46Vfs*22) and one whole gene deletion of MFSD8 confirmed by Sanger sequencing, genomic quantitative PCR and CNV-seq. Therefore, for nonconsanguineous CLN7 patients with homozygous mutations in the MFSD8 gene, genetic counseling staff should focus on the possibility of whole gene deletion. This is one case report describing a whole gene deletion in a Chinese patient with CLN7, suggesting the diagnosis of CLN7 should be based on clinical suspicion and genetic testing.
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Affiliation(s)
- Yimeng Qiao
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Yang Gu
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Ye Cheng
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Yu Su
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China
| | - Nan Lv
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Qing Shang
- Children's Hospital of Zhengzhou University and Henan Children's Hospital, Zhengzhou, China
| | - Qinghe Xing
- Institutes of Biomedical Sciences and Children's Hospital, Fudan University, Shanghai, China.,Shanghai Center for Women and Children's Health, Shanghai, China
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Kamate M, Reddy N, Detroja M, Hattiholi V. Neuronal Ceroid Lipofuscinoses in Children. Ann Indian Acad Neurol 2021; 24:192-197. [PMID: 34220062 PMCID: PMC8232483 DOI: 10.4103/aian.aian_61_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/08/2020] [Accepted: 02/10/2020] [Indexed: 11/22/2022] Open
Abstract
Background: The neuronal ceroid lipofuscinoses (NCL) constitute a group of gray matter neurodegenerative disorders characterized by the accumulation of ceroid lipopigment in lysosomes in neurons and other cell types. There are very few published studies on NCL from India, especially in children. Methods: A retrospective study of confirmed patients of NCL diagnosed over a period of 10 years from January 2019 to December 2019. Results: Fifty children had a definitive diagnosis of NCL based on enzymatic studies or genetic testing using next-generation sequencing. Around 15 children were diagnosed to have CLN-1 (ceroid lipofuscinoses, neuronal-1) based on palmitoyl protein thioesterase-1 deficiency; 24 children were diagnosed with CLN2 (ceroid lipofuscinoses, neuronal-2) based on deficient tripeptidyl-peptidase-1 activity; three patients were diagnosed as CLN6, five patients as CLN7, one case each of CLN8, CLN11, and CLN14 based on genetic testing. Clinical presentation was quite varied and included refractory seizures, developmental delay/regression, and abnormal movements. Visual failure was not common in the present case series. Neuroimaging patterns in different types of NCL were different. All children had a progressive downhill course resulting in death in many over a period of 5–10 years of disease onset. Conclusion: NCL is not uncommon and diagnosis can be suspected based on clinical investigations and neuroimaging findings. Diagnosis can be confirmed by enzymatic assays or genetic testing.
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Affiliation(s)
- Mahesh Kamate
- Division of Pediatric Neurology and In-Charge Child Development Clinic, Department of Pediatrics, KAHER's J N Medical College, Belgaum, Karnataka, India
| | - Narendranadha Reddy
- Department of Pediatrics, KAHER's J N Medical College, Belgaum, Karnataka, India
| | - Mayank Detroja
- Department of Child Development and Pediatric Neurology Centre, KLES PK Hospital, Belgaum, Karnataka, India
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Dev N, Kumar R, Sharma S, Sharma MC. Batten's disease: A seizure disorder's battle for diagnosis. Ann Indian Acad Neurol 2021; 24:953-955. [PMID: 35359518 PMCID: PMC8965944 DOI: 10.4103/aian.aian_769_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 07/27/2020] [Accepted: 08/07/2020] [Indexed: 11/04/2022] Open
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Johnson TB, Brudvig JJ, Lehtimäki KK, Cain JT, White KA, Bragge T, Rytkönen J, Huhtala T, Timm D, Vihma M, Puoliväli JT, Poutiainen P, Nurmi A, Weimer JM. A multimodal approach to identify clinically relevant biomarkers to comprehensively monitor disease progression in a mouse model of pediatric neurodegenerative disease. Prog Neurobiol 2020; 189:101789. [PMID: 32198061 DOI: 10.1016/j.pneurobio.2020.101789] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Revised: 01/21/2020] [Accepted: 03/13/2020] [Indexed: 12/24/2022]
Abstract
While research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single "needle in a haystack", we embrace the idea that disease progression, in mice and patients alike, is a diverse phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future.
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Affiliation(s)
- Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Jon J Brudvig
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | | | - Jacob T Cain
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Katherine A White
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Timo Bragge
- Discovery Research Services, Charles River, Kuopio, Finland
| | - Jussi Rytkönen
- Discovery Research Services, Charles River, Kuopio, Finland
| | - Tuulia Huhtala
- Discovery Research Services, Charles River, Kuopio, Finland
| | - Derek Timm
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Maria Vihma
- Discovery Research Services, Charles River, Kuopio, Finland
| | | | - Pekka Poutiainen
- Department of Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, Finland
| | - Antti Nurmi
- Discovery Research Services, Charles River, Kuopio, Finland.
| | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA; Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA.
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Jilani A, Matviychuk D, Blaser S, Dyack S, Mathieu J, Prasad AN, Prasad C, Kyriakopoulou L, Mercimek‐Andrews S. High diagnostic yield of direct Sanger sequencing in the diagnosis of neuronal ceroid lipofuscinoses. JIMD Rep 2019; 50:20-30. [PMID: 31741823 PMCID: PMC6850977 DOI: 10.1002/jmd2.12057] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/14/2019] [Accepted: 05/23/2019] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Neuronal ceroid lipofuscinoses are neurodegenerative disorders. To investigate the diagnostic yield of direct Sanger sequencing of the CLN genes, we reviewed Molecular Genetics Laboratory Database for molecular genetic test results of the CLN genes from a single clinical molecular diagnostic laboratory. METHODS We reviewed electronic patient charts. We used consent forms and Research Electronic Data Capture questionnaires for the patients from outside of our Institution. We reclassified all variants in the CLN genes. RESULTS Six hundred and ninety three individuals underwent the direct Sanger sequencing of the CLN genes for the diagnosis of neuronal ceroid lipofuscinoses. There were 343 symptomatic patients and 350 family members. Ninety-one symptomatic patients had molecular genetic diagnosis of neuronal ceroid lipofuscinoses including CLN1 (PPT1) (n = 10), CLN2 (TPP1) (n = 33), CLN3 (n = 17), CLN5 (n = 7), CLN6 (n = 10), CLN7 (MFSD8) (n = 10), and CLN8 (n = 4) diseases. The diagnostic yield of direct Sanger sequencing of CLN genes was 27% in symptomatic patients. We report detailed clinical and investigation results of 33 NCL patients. Juvenile onset CLN1 (PPT1) and adult onset CLN6 diseases were nonclassical phenotypes. CONCLUSION In our study, the diagnostic yield of direct Sanger sequencing was close to diagnostic yield of whole exome sequencing. Developmental regression, cognitive decline, visual impairment and cerebral and/or cerebellar atrophy in brain MRI are significant clinical and neuroimaging denominators to include NCL in the differential diagnosis.
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Affiliation(s)
- Abdulhakim Jilani
- Division of Clinical and Metabolic Genetics, Department of PaediatricsUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Diana Matviychuk
- Division of Genome Diagnostics, Department of Paediatric Laboratory MedicineThe Hospital for Sick ChildrenTorontoOntarioCanada
| | - Susan Blaser
- Division of Neuroradiology, Department of Medical ImagingUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
| | - Sarah Dyack
- Division of Medical Genetics, Department of Pediatrics, IWK Health CentreUniversity of DalhouiseHalifaxNova ScotiaCanada
| | - Jean Mathieu
- Neuromuscular Disease ClinicUniversity of SherbrookeQuebecCanada
| | - Asuri N. Prasad
- Division of Clinical Neurosciences, Department of Paediatrics, Schulich School of Medicine and DentistryWestern UniversityLondonOntarioCanada
| | - Chitra Prasad
- Division of Medical Genetics Department of Paediatrics, Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
| | - Lianna Kyriakopoulou
- Division of Genome Diagnostics, Department of Paediatric Laboratory MedicineThe Hospital for Sick ChildrenTorontoOntarioCanada
- Department of Paediatric Laboratory Medicine and PathobiologyUniversity of TorontoTorontoOntarioCanada
| | - Saadet Mercimek‐Andrews
- Division of Clinical and Metabolic Genetics, Department of PaediatricsUniversity of Toronto, The Hospital for Sick ChildrenTorontoOntarioCanada
- Genetics and Genome Biology Program, Research InstituteThe Hospital for Sick ChildrenTorontoOntarioCanada
- Institute of Medical SciencesUniversity of TorontoTorontoOntarioCanada
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Changes in motor behavior, neuropathology, and gut microbiota of a Batten disease mouse model following administration of acidified drinking water. Sci Rep 2019; 9:14962. [PMID: 31628420 PMCID: PMC6802212 DOI: 10.1038/s41598-019-51488-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 10/02/2019] [Indexed: 12/14/2022] Open
Abstract
CLN3 mutations cause the fatal neurodegenerative disorder, CLN3 Batten disease. The Cln3−/− mouse model displays characteristic features of the human disease including motor deficits. When mice received acidified drinking water (pH 2.5–2.9) instead of normal tap water (pH 8.4) for several generations, the motor skills of Cln3−/− mice normalized to control levels, indicating a disease-modifying effect of acidified water. Here we investigated if acidified water administered from postnatal day 21 has therapeutic benefits in Cln3−/− mice. Indeed, acidified water temporarily attenuated the motor deficits, had beneficial effects on behavioral parameters and prevented microglial activation in the brain of Cln3−/− mice. Interestingly, in control mice, acidified drinking water caused brain region-specific glial activation and significant changes in motor performance. Since the gut microbiota can influence neurological functions, we examined it in our disease model and found that the gut microbiota of Cln3−/− mice was markedly different from control mice, and acidified water differentially changed the gut microbiota composition in these mice. These results indicate that acidified water may provide therapeutic benefit to CLN3 Batten disease patients, and that the pH of drinking water is a major environmental factor that strongly influences the results of murine behavioral and pathological studies.
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CRISPR/Cas9 mediated generation of an ovine model for infantile neuronal ceroid lipofuscinosis (CLN1 disease). Sci Rep 2019; 9:9891. [PMID: 31289301 PMCID: PMC6616324 DOI: 10.1038/s41598-019-45859-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/12/2019] [Indexed: 01/09/2023] Open
Abstract
The neuronal ceroid lipofuscinoses (NCLs) are a group of devastating monogenetic lysosomal disorders that affect children and young adults with no cure or effective treatment currently available. One of the more severe infantile forms of the disease (INCL or CLN1 disease) is due to mutations in the palmitoyl-protein thioesterase 1 (PPT1) gene and severely reduces the child's lifespan to approximately 9 years of age. In order to better translate the human condition than is possible in mice, we sought to produce a large animal model employing CRISPR/Cas9 gene editing technology. Three PPT1 homozygote sheep were generated by insertion of a disease-causing PPT1 (R151X) human mutation into the orthologous sheep locus. This resulted in a morphological, anatomical and biochemical disease phenotype that closely resembles the human condition. The homozygous sheep were found to have significantly reduced PPT1 enzyme activity and accumulate autofluorescent storage material, as is observed in CLN1 patients. Clinical signs included pronounced behavioral deficits as well as motor deficits and complete loss of vision, with a reduced lifespan of 17 ± 1 months at a humanely defined terminal endpoint. Magnetic resonance imaging (MRI) confirmed a significant decrease in motor cortical volume as well as increased ventricular volume corresponding with observed brain atrophy and a profound reduction in brain mass of 30% at necropsy, similar to alterations observed in human patients. In summary, we have generated the first CRISPR/Cas9 gene edited NCL model. This novel sheep model of CLN1 disease develops biochemical, gross morphological and in vivo brain alterations confirming the efficacy of the targeted modification and potential relevance to the human condition.
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Johnson TB, Cain JT, White KA, Ramirez-Montealegre D, Pearce DA, Weimer JM. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol 2019; 15:161-178. [PMID: 30783219 PMCID: PMC6681450 DOI: 10.1038/s41582-019-0138-8] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Batten disease (also known as neuronal ceroid lipofuscinoses) constitutes a family of devastating lysosomal storage disorders that collectively represent the most common inherited paediatric neurodegenerative disorders worldwide. Batten disease can result from mutations in 1 of 13 genes. These mutations lead to a group of diseases with loosely overlapping symptoms and pathology. Phenotypically, patients with Batten disease have visual impairment and blindness, cognitive and motor decline, seizures and premature death. Pathologically, Batten disease is characterized by lysosomal accumulation of autofluorescent storage material, glial reactivity and neuronal loss. Substantial progress has been made towards the development of effective therapies and treatments for the multiple forms of Batten disease. In 2017, cerliponase alfa (Brineura), a tripeptidyl peptidase enzyme replacement therapy, became the first globally approved treatment for CLN2 Batten disease. Here, we provide an overview of the promising therapeutic avenues for Batten disease, highlighting current FDA-approved clinical trials and prospective future treatments.
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Affiliation(s)
- Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Jacob T Cain
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Katherine A White
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | | | - David A Pearce
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
- Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA.
| | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA.
- Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, SD, USA.
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Poppens MJ, Cain JT, Johnson TB, White KA, Davis SS, Laufmann R, Kloth AD, Weimer JM. Tracking sex-dependent differences in a mouse model of CLN6-Batten disease. Orphanet J Rare Dis 2019; 14:19. [PMID: 30665444 PMCID: PMC6341540 DOI: 10.1186/s13023-019-0994-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 01/07/2019] [Indexed: 02/08/2023] Open
Abstract
Background CLN6-Batten disease is a rare neurodevelopmental disorder characterized pathologically by the accumulation of lysosomal storage material, glial activation and neurodegeneration, and phenotypically by loss of vision, motor coordination, and cognitive ability, with premature death occurring in the second decade of life. In this study, we investigate whether sex differences in a mouse model of CLN6-Batten disease impact disease onset and progression. Results A number of noteworthy differences were observed including elevated accumulation of mitochondrial ATP synthase subunit C in the thalamus and cortex of female Cln6 mutant mice at 2 months of age. Moreover, female mutant mice showed more severe behavioral deficits. Beginning at 9 months of age, female mice demonstrated learning and memory deficits and suffered a more severe decline in motor coordination. Further, compared to their male counterparts, female animals succumbed to the disease at a slightly younger age, indicating an accelerated disease progression. Conversely, males showed a marked increase in microglial activation at 6 months of age in the cortex relative to females. Conclusions Thus, as female Cln6 mutant mice exhibit cellular and behavioral deficits that precede similar pathologies in male mutant mice, our findings suggest the need for consideration of sex-based differences in CLN6 disease progression during development of preclinical and clinical studies. Electronic supplementary material The online version of this article (10.1186/s13023-019-0994-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- McKayla J Poppens
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Jacob T Cain
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Tyler B Johnson
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Katherine A White
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Samantha S Davis
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | - Rachel Laufmann
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA
| | | | - Jill M Weimer
- Pediatrics and Rare Diseases Group, Sanford Research, Sioux Falls, SD, USA. .,Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD, USA.
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13
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Bosch ME, Kielian T. Astrocytes in juvenile neuronal ceroid lipofuscinosis (CLN3) display metabolic and calcium signaling abnormalities. J Neurochem 2018; 148:612-624. [PMID: 29964296 DOI: 10.1111/jnc.14545] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2017] [Revised: 05/21/2018] [Accepted: 06/22/2018] [Indexed: 12/11/2022]
Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a lysosomal storage disease caused by autosomal recessive mutations in ceroid lipofuscinosis 3 (CLN3). Children with JNCL experience progressive visual, cognitive, and motor deterioration with a decreased life expectancy (late teens-early 20s). Neuronal loss is thought to occur, in part, via glutamate excitotoxicity; however, little is known about astrocyte glutamate regulation in JNCL. Spontaneous Ca2+ oscillations were reduced in murine Cln3Δex7/8 astrocytes, which were also observed following glutamate or cytokine exposure. Astrocyte glutamate transport is an energy-demanding process and disruptions in metabolic pathways could influence glutamate homeostasis in Cln3Δex7/8 astrocytes. Indeed, basal mitochondrial respiration and ATP production were significantly reduced in Cln3Δex7/8 astrocytes. These changes were not attributable to reduced mitochondria, since mitochondrial DNA levels were similar between wild type and Cln3Δex7/8 astrocytes. Interestingly, despite these functional deficits in Cln3Δex7/8 astrocytes, glutamate transporter expression and glutamate uptake were not dramatically affected. Concurrent with impaired astrocyte metabolism and Ca2+ signaling, murine Cln3Δex7/8 neurons were hyper-responsive to glutamate, as reflected by heightened and prolonged Ca2+ signals. These findings identify intrinsic metabolic and Ca2+ signaling defects in Cln3Δex7/8 astrocytes that may contribute to neuronal dysfunction in CLN3 disease. This article is part of the Special Issue "Lysosomal Storage Disorders".
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Affiliation(s)
- Megan E Bosch
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Tammy Kielian
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
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14
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Nickel M, Simonati A, Jacoby D, Lezius S, Kilian D, Van de Graaf B, Pagovich OE, Kosofsky B, Yohay K, Downs M, Slasor P, Ajayi T, Crystal RG, Kohlschütter A, Sondhi D, Schulz A. Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: an observational cohort study. THE LANCET. CHILD & ADOLESCENT HEALTH 2018; 2:582-590. [PMID: 30119717 PMCID: PMC7516285 DOI: 10.1016/s2352-4642(18)30179-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Revised: 05/23/2018] [Accepted: 05/23/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.
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Affiliation(s)
- Miriam Nickel
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alessandro Simonati
- Department of Neuroscience, Biomedicine, Movement-Neurology (Child Neurology and Psychiatry, and Neuropathology), University of Verona, Verona, Italy
| | | | - Susanne Lezius
- Department of Biometrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dirk Kilian
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Odelya E Pagovich
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Barry Kosofsky
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Kaleb Yohay
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA; Department of Neurology, New York University, Langone Medical Center, New York, NY, USA
| | | | | | | | - Ronald G Crystal
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Alfried Kohlschütter
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dolan Sondhi
- Department of Genetic Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Angela Schulz
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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15
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Lack of specificity of antibodies raised against CLN3, the lysosomal/endosomal transmembrane protein mutated in juvenile Batten disease. Biosci Rep 2017; 37:BSR20171229. [PMID: 29089465 PMCID: PMC5700270 DOI: 10.1042/bsr20171229] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2017] [Revised: 10/24/2017] [Accepted: 10/26/2017] [Indexed: 11/17/2022] Open
Abstract
Juvenile CLN3 (Batten) disease, a fatal, childhood neurodegenerative disorder, results from mutations in the CLN3 gene encoding a lysosomal/endosomal transmembrane protein. The exact physiological function of CLN3 is still unknown and it is unclear how CLN3 mutations lead to selective neurodegeneration. To study the tissue expression and subcellular localization of the CLN3 protein, a number of anti-CLN3 antibodies have been generated using either the whole CLN3 protein or short peptides from CLN3 for immunization. The specificity of these antibodies, however, has never been tested properly. Using immunoblot experiments, we show that commercially available or researcher-generated anti-CLN3 antibodies lack specificity: they detect the same protein bands in wild-type (WT) and Cln3−/− mouse brain and kidney extracts prepared with different detergents, in membrane proteins isolated from the cerebellum, cerebral hemisphere and kidney of WT and Cln3−/− mice, in cell extracts of WT and Cln3−/− mouse embryonic fibroblast cultures, and in lysates of BHK cells lacking or overexpressing human CLN3. Protein BLAST searches with sequences from peptides used to generate anti-CLN3 antibodies identified short motifs present in a number of different mouse and human proteins, providing a plausible explanation for the lack of specificity of anti-CLN3 antibodies. Our data provide evidence that immunization against a transmembrane protein with low to medium expression level does not necessarily generate specific antibodies. Because of the possible cross-reactivity to other proteins, the specificity of an antibody should always be checked using tissue samples from an appropriate knock-out animal or using knock-out cells.
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16
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Pharmacological Effects on Ceroid Lipofuscin and Neuronal Structure in Cln3 ∆ex7/8 Mouse Brain Cultures. J Mol Neurosci 2017; 63:100-114. [DOI: 10.1007/s12031-017-0962-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 07/31/2017] [Indexed: 10/19/2022]
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17
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Hirz M, Drögemüller M, Schänzer A, Jagannathan V, Dietschi E, Goebel HH, Hecht W, Laubner S, Schmidt MJ, Steffen F, Hilbe M, Köhler K, Drögemüller C, Herden C. Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog. Mol Genet Metab 2017; 120:269-277. [PMID: 28024876 DOI: 10.1016/j.ymgme.2016.12.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2016] [Revised: 12/14/2016] [Accepted: 12/15/2016] [Indexed: 11/20/2022]
Abstract
Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenländische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known.
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Affiliation(s)
- M Hirz
- Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany.
| | - M Drögemüller
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland
| | - A Schänzer
- Institute of Neuropathology, Justus-Liebig-University Giessen, Germany
| | - V Jagannathan
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland
| | - E Dietschi
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland
| | - H H Goebel
- Institute of Neuropathology Charité, University Berlin, Germany
| | - W Hecht
- Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany
| | - S Laubner
- Clinic for Small Animals - Surgery, Justus-Liebig-University Giessen, Germany
| | - M J Schmidt
- Clinic for Small Animals - Surgery, Justus-Liebig-University Giessen, Germany
| | - F Steffen
- Clinic for Small Animals - Neurology, Vetsuisse Faculty, University of Zurich, Switzerland
| | - M Hilbe
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Switzerland
| | - K Köhler
- Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany
| | - C Drögemüller
- Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland
| | - C Herden
- Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany
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18
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Baker EH, Levin SW, Zhang Z, Mukherjee AB. MRI Brain Volume Measurements in Infantile Neuronal Ceroid Lipofuscinosis. AJNR Am J Neuroradiol 2016; 38:376-382. [PMID: 27765741 DOI: 10.3174/ajnr.a4978] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 08/29/2016] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N-acetyl cysteine, we made serial measurements of patients' brain volumes with MR imaging. MATERIALS AND METHODS Ten patients with infantile neuronal ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients' brain volumes were compared with those of a healthy population. RESULTS Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.
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Affiliation(s)
- E H Baker
- From the Department of Radiology and Imaging Sciences (E.H.B.), Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - S W Levin
- Program on Endocrinology and Molecular Genetics (S.W.L., Z.Z., A.B.M.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Z Zhang
- Program on Endocrinology and Molecular Genetics (S.W.L., Z.Z., A.B.M.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - A B Mukherjee
- Program on Endocrinology and Molecular Genetics (S.W.L., Z.Z., A.B.M.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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19
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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.
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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.
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20
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Cesta MF, Mozzachio K, Little PB, Olby NJ, Sills RC, Brown TT. Neuronal Ceroid Lipofuscinosis in a Vietnamese Pot-bellied Pig (Sus scrofa). Vet Pathol 2016; 43:556-60. [PMID: 16847000 DOI: 10.1354/vp.43-4-556] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The neuronal ceroid ipofuscinoses (NCL) are a group of heritable, neurodegenerative, storage diseases, typically with an autosomal recessive mode of inheritance. Cytoplasmic accumulation of storage material in cells of the nervous system and, variably in other tissues, characterizes NCL. NCL has been reported in many animal species, but to the authors' knowledge, this is the first report of the disease in a pig. Blindness and seizures are common clinical signs of disease, neither of which was a feature in this pig. The lesions were restricted to the central nervous system, which was diffusely affected, with the most severe lesions in the hippocampus, cerebral cortex, and cerebellum. The histologic lesions included neuronal loss and gliosis, which contributed to mild cerebrocortical and cerebellar atrophy and accumulation of autofluorescent storage material in neurons and glial cells. The storage material had morphologic, histologic, and ultrastructural properties typical of NCL.
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Affiliation(s)
- M F Cesta
- Integrated Laboratory Systems, Inc., PO Box 13501, Research Triangle Park, NC 27709 (USA).
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21
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Kovács AD, Pearce DA. Finding the most appropriate mouse model of juvenile CLN3 (Batten) disease for therapeutic studies: the importance of genetic background and gender. Dis Model Mech 2016; 8:351-61. [PMID: 26035843 PMCID: PMC4381334 DOI: 10.1242/dmm.018804] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Mutations in the CLN3 gene cause a fatal neurodegenerative disorder: juvenile CLN3 disease, also known as juvenile Batten disease. The two most commonly utilized mouse models of juvenile CLN3 disease are Cln3-knockout (Cln3−/−) and Cln3Δex7/8-knock-in mice, the latter mimicking the most frequent disease-causing human mutation. To determine which mouse model has the most pronounced neurological phenotypes that can be used as outcome measures for therapeutic studies, we compared the exploratory activity, motor function and depressive-like behavior of 1-, 3- and 6-month-old Cln3−/− and Cln3Δex7/8-knock-in mice on two different genetic backgrounds (129S6/SvEv and C57BL/6J). Although, in many cases, the behavior of Cln3−/− and Cln3Δex7/8 mice was similar, we found genetic-background-, gender- and age-dependent differences between the two mouse models. We also observed large differences in the behavior of the 129S6/SvEv and C57BL/6J wild-type strains, which highlights the strong influence that genetic background can have on phenotype. Based on our results, Cln3−/− male mice on the 129S6/SvEv genetic background are the most appropriate candidates for therapeutic studies. They exhibit motor deficits at 1 and 6 months of age in the vertical pole test, and they were the only mice to show impaired motor coordination in the rotarod test at both 3 and 6 months. Cln3−/− males on the C57BL/6J background and Cln3Δex7/8 males on the 129S6/SvEv background also provide good outcome measures for therapeutic interventions. Cln3−/− (C57BL/6J) males had serious difficulties in climbing down (at 1 and 6 months) and turning downward on (at 1, 3 and 6 months) the vertical pole, whereas Cln3Δex7/8 (129S6/SvEv) males climbed down the vertical pole drastically slower than wild-type males at 3 and 6 months of age. Our study demonstrates the importance of testing mouse models on different genetic backgrounds and comparing males and females in order to find the most appropriate disease model for therapeutic studies.
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Affiliation(s)
- Attila D Kovács
- Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA
| | - David A Pearce
- Sanford Children's Health Research Center, Sanford Research, Sioux Falls, SD 57104, USA. Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA.
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22
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Baker EH, Levin SW, Zhang Z, Mukherjee AB. Evaluation of disease progression in INCL by MR spectroscopy. Ann Clin Transl Neurol 2015; 2:797-809. [PMID: 26339674 PMCID: PMC4554441 DOI: 10.1002/acn3.222] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 05/13/2015] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase-1 deficiency, which impairs degradation of palmitoylated proteins (constituents of ceroid) by lysosomal hydrolases. Consequent lysosomal ceroid accumulation leads to neuronal injury. As part of a pilot study to evaluate treatment benefits of cysteamine bitartrate and N-acetylcysteine, we quantitatively measured brain metabolite levels using magnetic resonance spectroscopy (MRS). METHODS A subset of two patients from a larger treatment and follow-up study underwent serial quantitative single-voxel MRS examinations of five anatomical sites. Three echo times were acquired in order to estimate metabolite T2. Measured metabolite levels included correction for partial volume of cerebrospinal fluid. Comparison of INCL patients was made to a reference group composed of asymptomatic and minimally symptomatic Niemann-Pick disease type C patients. RESULTS In INCL patients, N-acetylaspartate (NAA) was abnormally low at all locations upon initial measurement, and further declined throughout the follow-up period. In the cerebrum (affected early in the disease course), choline and myo-inositol were initially elevated and fell during the follow-up period, whereas in the cerebellum and brainstem (affected later), choline and myo-inositol were initially normal and rose subsequently. INTERPRETATION Choline and myo-inositol levels in our patients are consistent with patterns of neuroinflammation observed in two INCL mouse models. Low, persistently declining NAA was expected based on the progressive, irreversible nature of the disease. Progression of metabolite levels in INCL has not been previously quantified; therefore the results of this study serve as a reference for quantitative evaluation of future therapeutic interventions.
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Affiliation(s)
- Eva H Baker
- Department of Radiology and Imaging Sciences, Clinical Center, National Institutes of Health Bethesda, Maryland, USA, 20892
| | - Sondra W Levin
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892 ; Department of Pediatrics, Walter Reed National Military Medical Center Bethesda, Maryland, USA, 20889-5600
| | - Zhongjian Zhang
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892
| | - Anil B Mukherjee
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH Bethesda, Maryland, USA, 20892
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23
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Richa F. Anaesthesia and orphan disease: a child with neuronal ceroid lipofuscinosis. Eur J Anaesthesiol 2015; 32:213-215. [PMID: 24979587 DOI: 10.1097/eja.0000000000000111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Affiliation(s)
- Freda Richa
- From the Saint-Joseph University, Hotel-Dieu de France Hospital, Anaesthesia and Intensive Care Department, Beirut, Lebanon
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24
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Craiu D, Dragostin O, Dica A, Hoffman-Zacharska D, Gos M, Bastian AE, Gherghiceanu M, Rolfs A, Nahavandi N, Craiu M, Iliescu C. Rett-like onset in late-infantile neuronal ceroid lipofuscinosis (CLN7) caused by compound heterozygous mutation in the MFSD8 gene and review of the literature data on clinical onset signs. Eur J Paediatr Neurol 2015; 19:78-86. [PMID: 25439737 DOI: 10.1016/j.ejpn.2014.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 07/16/2014] [Accepted: 07/27/2014] [Indexed: 02/05/2023]
Abstract
BACKGROUND We present clinical and molecular findings of a patient with ceroid-lipofuscinosis CLN7, with a compound heterozygous mutation of the MFSD8 gene, with Rett syndrome clinical signs onset and a later development of full picture of vLINCL. CASE PRESENTATION A 7 years-old female patient with normal development until the age 12 months, developed Rett like clinical picture (psychomotor regression, microcephaly, stereotypic hands movements in the midline, hyperventilation episodes) present at the onset of her condition (age 18 months), features still present at the initial evaluation in our clinic at age 5 years. RESULTS MECP2 (methyl CpG binding protein 2) gene mutation was negative. At age 6 years she was readmitted for severe ataxia and blindness, seizures, and severe developmental regression leading to NCL (neuronal ceroid lipofuscinosis) suspicion. EEG showed slow background with IRDA (intermittent rhythmic delta activity). A conjunctive biopsy showed abnormal curvilinear and fingerprint lysosomal deposits, and genetic analysis revealed two heterozygous mutations of MFSD8 gene (c.881C > A p.Thr294Lys and c.754 + 2T > A) each inherited from carrier parents and a heterozygous variant (c.470A>C p.Asp157Ala) of CLN5 gene. CONCLUSION NCL should be suspected and MFSD8 genetic testing should also be considered in patients with Rett like phenotype at onset and negative MECP2 mutation. Such cases should be carefully and frequently re-evaluated in order to avoid delayed diagnosis and offer proper genetic advice to the family. In our knowledge, this might be the first case of CLN7 disease with Rett like onset described in the literature, which developed typical vLINCL clinical phenotype after age 5.5 years. A short review of the literature showing NCL onset modalities is presented.
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Affiliation(s)
- Dana Craiu
- "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Octavia Dragostin
- Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Alice Dica
- Pediatric Neurology Clinic, Research Department, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
| | - Dorota Hoffman-Zacharska
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland.
| | - Monika Gos
- Department of Medical Genetics, Institute of Mother and Child, Kasprzaka 17A, 01-211 Warsaw, Poland.
| | - Alexandra Eugenia Bastian
- "Carol Davila" University of Medicine Bucharest, Department II, Dental Medicine, Pathology Discpline, Romania; Pathology Lab., Colentina University Hospital, Sos Stefan cel Mare 19-21, Sector 2, 020125 Bucharest, Romania.
| | - Mihaela Gherghiceanu
- Ultrastructural Pathology Lab., 'Victor Babes' National Institute of Pathology, 99-101 Spl. Independentei, 050096 Bucharest 5, Romania.
| | - Arndt Rolfs
- Albrecht-Kossel-Institute for Neurogenetics, Medical Faculty, University of Rostock, Gehlsheimerstrasse 20, 18157 Rostock, Germany; Centogene AG, Schillingallee 69, 18057 Rostock, Germany.
| | | | - Mihai Craiu
- "Carol Davila" University of Medicine Bucharest, Department of Pediatrics and Medical Genetics, Discipline Pediatrics, Romania; Pediatric II Clinic, "Alfred Rusescu" Clinical Pediatric Hospital, Institute of Mother and Child Health, B-dul Lacul Tei No. 120, Sector 2, Bucharest, Romania.
| | - Catrinel Iliescu
- "Carol Davila" University of Medicine Bucharest, Department of Neurology, Pediatric Neurology, Psychiatry, Neurosurgery, Discipline Pediatric Neurology, Romania; Pediatric Neurology Clinic, "Alexandru Obregia" Clinical Psychiatric Hospital, Şos. Berceni 10-12, Sector 4, Bucharest, Romania.
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Bouchelion A, Zhang Z, Li Y, Qian H, Mukherjee AB. Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype. Ann Clin Transl Neurol 2014; 1:1006-23. [PMID: 25574475 PMCID: PMC4284126 DOI: 10.1002/acn3.144] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Accepted: 10/16/2014] [Indexed: 11/21/2022] Open
Abstract
Objective Nonsense mutations account for 5–70% of all genetic disorders. In the United States, nonsense mutations in the CLN1/PPT1 gene underlie >40% of the patients with infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative lysosomal storage disease. We sought to generate a reliable mouse model of INCL carrying the most common Ppt1 nonsense mutation (c.451C>T) found in the United States patient population to provide a platform for evaluating nonsense suppressors in vivo. Methods We knocked-in c.451C>T nonsense mutation in the Ppt1 gene in C57 embryonic stem (ES) cells using a targeting vector in which LoxP flanked the Neo cassette, which was removed from targeted ES cells by electroporating Cre. Two independently targeted ES clones were injected into blastocysts to generate syngenic C57 knock-in mice, obviating the necessity for extensive backcrossing. Results Generation of Ppt1-KI mice was confirmed by DNA sequencing, which showed the presence of c.451C>T mutation in the Ppt1 gene. These mice are viable and fertile, although they developed spasticity (a “clasping” phenotype) at a median age of 6 months. Autofluorescent storage materials accumulated throughout the brain regions and in visceral organs. Electron microscopic analysis of the brain and the spleen showed granular osmiophilic deposits. Increased neuronal apoptosis was particularly evident in cerebral cortex and abnormal histopathological and electroretinographic (ERG) analyses attested striking retinal degeneration. Progressive deterioration of motor coordination and behavioral parameters continued until eventual death. Interpretation Our findings show that Ppt1-KI mice reliably recapitulate INCL phenotype providing a platform for testing the efficacy of existing and novel nonsense suppressors in vivo.
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Affiliation(s)
- Ashleigh Bouchelion
- Program on Developmental Endocrinology and Genetics, Section on Developmental Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development Bethesda, Maryland
| | - Zhongjian Zhang
- Program on Developmental Endocrinology and Genetics, Section on Developmental Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development Bethesda, Maryland
| | - Yichao Li
- Visual Function Core (HNW2-L), National Eye Institute, National Institutes of Health Bethesda, Maryland, 20892-1830
| | - Haohua Qian
- Visual Function Core (HNW2-L), National Eye Institute, National Institutes of Health Bethesda, Maryland, 20892-1830
| | - Anil B Mukherjee
- Program on Developmental Endocrinology and Genetics, Section on Developmental Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development Bethesda, Maryland
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Guo J, Johnson GS, Brown HA, Provencher ML, da Costa RC, Mhlanga-Mutangadura T, Taylor JF, Schnabel RD, O'Brien DP, Katz ML. A CLN8 nonsense mutation in the whole genome sequence of a mixed breed dog with neuronal ceroid lipofuscinosis and Australian Shepherd ancestry. Mol Genet Metab 2014; 112:302-9. [PMID: 24953404 DOI: 10.1016/j.ymgme.2014.05.014] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 05/28/2014] [Accepted: 05/28/2014] [Indexed: 01/03/2023]
Abstract
The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the opportunity for identifying dogs that can be used to establish a canine model for the CLN8 disease (also known as late infantile variant or late infantile CLN8 disease).
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Affiliation(s)
- Juyuan Guo
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - Gary S Johnson
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - Holly A Brown
- Metz Petz Veterinary Clinic at Shawnee, Lima, OH, USA
| | - Michele L Provencher
- Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, Columbus, OH, USA
| | - Ronaldo C da Costa
- Department of Veterinary Clinical Sciences, The Ohio State University College of Veterinary Medicine, Columbus, OH, USA
| | - Tendai Mhlanga-Mutangadura
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - Jeremy F Taylor
- Division of Animal Science, University of Missouri College of Agriculture, Food and Natural Resources, Columbia, MO, USA
| | - Robert D Schnabel
- Division of Animal Science, University of Missouri College of Agriculture, Food and Natural Resources, Columbia, MO, USA
| | - Dennis P O'Brien
- Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA
| | - Martin L Katz
- Mason Eye Institute, University of Missouri School of Medicine, Columbia, MO, USA.
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Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused by mutations in the CLN3 gene, which encodes for a putative lysosomal transmembrane protein with thus far undescribed structure and function. Here we investigate the membrane topology of human CLN3 protein with a combination of advanced molecular cloning, spectroscopy, and in silico computation. Using the transposomics cloning method we first created a library of human CLN3 cDNA clones either with a randomly inserted eGFP, a myc-tag, or both. The functionality of the clones was evaluated by assessing their ability to revert a previously reported lysosomal phenotype in immortalized cerebellar granular cells derived from Cln3Δex7/8 mice (CbCln3Δex7/8). The double-tagged clones were expressed in HeLa cells, and FRET was measured between the donor eGFP and an acceptor DyLight547 coupled to a monoclonal α-myc antibody to assess their relative membrane orientation. The data were used together with previously reported experimental data to compile a constrained membrane topology model for hCLN3 using TOPCONS consensus membrane prediction algorithm. Our model with six transmembrane domains and cytosolic N- and C-termini largely agrees with those previously suggested but differs in terms of the transmembrane domain positions as well as in the size of the luminal loops. This finding improves understanding the function of the native hCLN3 protein.
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Levin SW, Baker EH, Zein WM, Zhang Z, Quezado ZMN, Miao N, Gropman A, Griffin KJ, Bianconi S, Chandra G, Khan OI, Caruso RC, Liu A, Mukherjee AB. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol 2014; 13:777-87. [PMID: 24997880 DOI: 10.1016/s1474-4422(14)70142-5] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Infantile neuronal ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene (CLN1 or PPT1) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal ceroid lipofuscinosis. METHODS Children between 6 months and 3 years of age with infantile neuronal ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6-12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. FINDINGS Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. INTERPRETATION Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. FUNDING National Institutes of Health.
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Affiliation(s)
- Sondra W Levin
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA; Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD, USA
| | - Eva H Baker
- Department of Radiology and Imaging Sciences, NIH Clinical Center, NIH, Bethesda, MD, USA
| | | | - Zhongjian Zhang
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA
| | - Zenaide M N Quezado
- Department of Anesthesiology, NIH Clinical Center, NIH, Bethesda, MD, USA; Department of Anesthesiology, Children's National Medical Center, Washington, DC, USA
| | - Ning Miao
- Department of Anesthesiology, NIH Clinical Center, NIH, Bethesda, MD, USA
| | - Andrea Gropman
- National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA; Department of Neurology, Children's National Medical Center, Washington, DC, USA
| | - Kurt J Griffin
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA; Sanford Research/University of South Dakota Medical Center, Sioux Falls, SD, USA
| | - Simona Bianconi
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA
| | - Goutam Chandra
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA
| | - Omar I Khan
- National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA
| | - Rafael C Caruso
- National Eye Institute, NIH, Bethesda, MD, USA; Department of Psychology, Princeton University, Princeton, NJ, USA
| | - Aiyi Liu
- Biostatistics and Bioinformatics Branch, Eunice Kennedy-Shriver NICHD, NIH, Bethesda, MD, USA
| | - Anil B Mukherjee
- Program on Developmental Endocrinology and Genetics, Eunice Kennedy-Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, MD, USA.
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Héraud C, Griffiths A, Pandruvada SNM, Kilimann MW, Pata M, Vacher J. Severe neurodegeneration with impaired autophagy mechanism triggered by ostm1 deficiency. J Biol Chem 2014; 289:13912-25. [PMID: 24719316 DOI: 10.1074/jbc.m113.537233] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Loss of Ostm1 leads to the most severe form of osteopetrosis in mice and humans. Because functional rescue of the osteopetrotic defect in these mice extended their lifespan from ∼3 weeks to 6 weeks, this unraveled a second essential role of Ostm1. We discovered that Ostm1 is highly expressed in the mouse brain in neurons, microglia, and astrocytes. At 3-4 weeks of age, mice with Ostm1 loss showed 3-10-fold stimulation of reactive gliosis, with an increased astrocyte cell population and microglia activation. This inflammatory response was associated with marked retinal photoreceptor degeneration and massive neuronal loss in the brain. Intracellular characterization of neurons revealed abnormal storage of carbohydrates, lipids, and ubiquitinated proteins, combined with marked accumulation of autophagosomes that causes frequent axonal swelling. Stimulation of autophagy was provided by specific markers and by significant down-regulation of the mammalian target of rapamycin signaling, identifying a cellular pathologic mechanism. A series of transgenic mouse lines specifically targeted to distinct central nervous system cell subpopulations determined that Ostm1 has a primary and autonomous role in neuronal homeostasis. Complete functional complementation demonstrated that the development of severe and rapid neurodegeneration in these mice is independent of the hematopoietic lineage and has clinical implications for treatment of osteopetrosis. Importantly, this study establishes a novel neurodegenerative mouse model critical for understanding the multistep pathogenic cascade of cellular autophagy disorders toward therapeutic strategy design.
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Affiliation(s)
- Céline Héraud
- From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Adam Griffiths
- From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Subramanya N M Pandruvada
- From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Manfred W Kilimann
- the Department of Otolaryngology, Göttingen University Medical Center, D-37075 Göttingen, Germany, and the Department of Molecular Neurobiology, Max-Planck-Institute for Experimental Medicine, D-37075 Göttingen, Germany
| | - Monica Pata
- From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Jean Vacher
- From the Institut de Recherches Cliniques de Montréal (IRCM), Département de Médecine, Université de Montréal, Montréal, Québec H2W 1R7, Canada, the Department of Medicine, Division of Experimental Medicine, McGill University, Montréal, Québec H3A 1A3, Canada,
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Alroy J, Lyons JA. Lysosomal Storage Diseases. JOURNAL OF INBORN ERRORS OF METABOLISM AND SCREENING 2014. [DOI: 10.1177/2326409813517663] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Joseph Alroy
- Department of Pathology, Tufts University School of Medicine1, Boston, MA, USA
- Tufts Medical Center, Boston, MA, USA
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
| | - Jeremiah A. Lyons
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA
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Jadav RH, Sinha S, Yasha TC, Aravinda H, Gayathri N, Rao S, Bindu PS, Satishchandra P. Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes. Pediatr Neurol 2014; 50:85-95. [PMID: 24120650 DOI: 10.1016/j.pediatrneurol.2013.08.008] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 08/05/2013] [Accepted: 08/07/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE We evaluated the clinical, electrophysiological, imaging, and ultrastructural features of neuronal ceroid lipofuscinoses and its subtypes. METHODS The clinical, electrophysiological, imaging, histopathological, and ultrastructural features of 68 (age at onset: 4.3 ± 5.4 years) neuronal ceroid lipofuscinoses and its subtypes (infantile neuronal ceroid lipofuscinoses [9], late infantile neuronal ceroid lipofuscinoses [34], juvenile neuronal ceroid lipofuscinoses [23], and adult neuronal ceroid lipofuscinoses [2] were evaluated. Skin (n = 56), brain (n = 12), muscle (n = 4) and nerve (n = 1) biopsies confirmed the diagnosis. RESULTS Clinical manifestations were milestone regression (93%), involuntary movements (92%), seizures (89%), myoclonus (79%), and visual impairment (68%). Response to anticonvulsants was unsatisfactory. Electroencephalography (n = 59) was abnormal in 90%: background slowing (90%); epileptiform discharges (71%), and photoparoxysmal response (4/21). Visual-evoked (n = 33) and somatosensory evoked (n = 40) potentials were abnormal in 62% and 63% of patients. Cranial computed tomography (n = 33) showed diffuse cerebral (61%) and cerebellar (27%) atrophy. Magnetic resonance imaging was abnormal in all 43 patients who were scanned: diffuse atrophy (100%), cerebellar atrophy (40%), leukoencephalopathy (65%), and thalamic T2 W hypointensity (33%). Dermal inclusions such as curvilinear inclusions were the most common abnormality: late infantile neuronal ceroid lipofuscinoses (97%), juvenile neuronal ceroid lipofuscinoses (100%), and infantile neuronal ceroid lipofuscinoses (88%). Additional fingerprint inclusions were noted: juvenile neuronal ceroid lipofuscinoses (43%), late infantile neuronal ceroid lipofuscinoses (15%), and infantile neuronal ceroid lipofuscinoses (13%). Granular osmiophilic deposits were noted in 50% of infantile neuronal ceroid lipofuscinoses. In 75% of patients, there was good correlation between the clinical subtype and ultrastructural inclusion pattern. In 27% of neuronal ceroid lipofuscinoses, multiple inclusions were noted. CONCLUSIONS The diagnosis of neuronal ceroid lipofuscinoses should be considered in individuals with characteristic clinical presentations and characteristic ultrastructural dermal inclusions. Three fourths showed morphological correlation of the inclusions with neuronal ceroid lipofuscinoses subtype.
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Affiliation(s)
- Rakesh H Jadav
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Sanjib Sinha
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
| | - T C Yasha
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - H Aravinda
- Department of Neuroimaging and Interventional Radiology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - N Gayathri
- Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - S Rao
- Department of Biostatistics, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - P S Bindu
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - P Satishchandra
- Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India
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Stauber T, Weinert S, Jentsch TJ. Cell biology and physiology of CLC chloride channels and transporters. Compr Physiol 2013; 2:1701-44. [PMID: 23723021 DOI: 10.1002/cphy.c110038] [Citation(s) in RCA: 115] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Proteins of the CLC gene family assemble to homo- or sometimes heterodimers and either function as Cl(-) channels or as Cl(-)/H(+)-exchangers. CLC proteins are present in all phyla. Detailed structural information is available from crystal structures of bacterial and algal CLCs. Mammals express nine CLC genes, four of which encode Cl(-) channels and five 2Cl(-)/H(+)-exchangers. Two accessory β-subunits are known: (1) barttin and (2) Ostm1. ClC-Ka and ClC-Kb Cl(-) channels need barttin, whereas Ostm1 is required for the function of the lysosomal ClC-7 2Cl(-)/H(+)-exchanger. ClC-1, -2, -Ka and -Kb Cl(-) channels reside in the plasma membrane and function in the control of electrical excitability of muscles or neurons, in extra- and intracellular ion homeostasis, and in transepithelial transport. The mainly endosomal/lysosomal Cl(-)/H(+)-exchangers ClC-3 to ClC-7 may facilitate vesicular acidification by shunting currents of proton pumps and increase vesicular Cl(-) concentration. ClC-3 is also present on synaptic vesicles, whereas ClC-4 and -5 can reach the plasma membrane to some extent. ClC-7/Ostm1 is coinserted with the vesicular H(+)-ATPase into the acid-secreting ruffled border membrane of osteoclasts. Mice or humans lacking ClC-7 or Ostm1 display osteopetrosis and lysosomal storage disease. Disruption of the endosomal ClC-5 Cl(-)/H(+)-exchanger leads to proteinuria and Dent's disease. Mouse models in which ClC-5 or ClC-7 is converted to uncoupled Cl(-) conductors suggest an important role of vesicular Cl(-) accumulation in these pathologies. The important functions of CLC Cl(-) channels were also revealed by human diseases and mouse models, with phenotypes including myotonia, renal loss of salt and water, deafness, blindness, leukodystrophy, and male infertility.
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Affiliation(s)
- Tobias Stauber
- Leibniz-Institut für Molekulare Pharmakologie FMP and Max-Delbrück-Centrum für Molekulare Medizin MDC, Berlin, Germany
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Wang R, Borazjani A, Matthews AT, Mangum LC, Edelmann MJ, Ross MK. Identification of palmitoyl protein thioesterase 1 in human THP1 monocytes and macrophages and characterization of unique biochemical activities for this enzyme. Biochemistry 2013; 52:7559-74. [PMID: 24083319 DOI: 10.1021/bi401138s] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The profiles of serine hydrolases in human and mouse macrophages are similar yet different. For instance, human macrophages express high levels of carboxylesterase 1 (CES1), whereas mouse macrophages have minimal amounts of the orthologous murine CES1. On the other hand, macrophages from both species exhibit limited expression of the canonical 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, MAGL. Our previous study showed CES1 was partly responsible for the hydrolysis of 2-AG (50%) and prostaglandin glyceryl esters (PG-Gs) (80-95%) in human THP1 monocytes and macrophages. However, MAGL and other endocannabinoid hydrolases, FAAH, ABHD6, and ABHD12, did not have a role because of limited expression or no expression. Thus, another enzyme was hypothesized to be responsible for the remaining 2-AG hydrolysis activity following chemical inhibition and immunodepletion of CES1 (previous study) or CES1 gene knockdown (this study). Here we identified two candidate serine hydrolases in THP1 cell lysates by activity-based protein profiling (ABPP)-MUDPIT and Western blotting: cathepsin G and palmitoyl protein thioesterase 1 (PPT1). Both proteins exhibited electrophoretic properties similar to those of a serine hydrolase in THP1 cells detected by gel-based ABPP at 31-32 kDa; however, only PPT1 exhibited lipolytic activity and hydrolyzed 2-AG in vitro. Interestingly, PPT1 was strongly expressed in THP1 cells but was significantly less reactive than cathepsin G toward the activity-based probe, fluorophosphonate-biotin. KIAA1363, another serine hydrolase, was also identified in THP1 cells but did not have significant lipolytic activity. On the basis of chemoproteomic profiling, immunodepletion studies, and chemical inhibitor profiles, we estimated that PPT1 contributed 32-40% of 2-AG hydrolysis activity in the THP1 cell line. In addition, pure recombinant PPT1 catalyzed the hydrolysis of 2-AG, PGE2-G, and PGF2α-G, although the catalytic efficiency of hydrolysis of 2-AG by PPT1 was ~10-fold lower than that of CES1. PPT1 was also insensitive to several chemical inhibitors that potently inhibit CES1, such as organophosphate poisons and JZL184. This is the first report to document the expression of PPT1 in a human monocyte and macrophage cell line and to show PPT1 can hydrolyze the natural substrates 2-AG and PG-Gs. These findings suggest that PPT1 may participate in endocannabinoid metabolism within specific cellular contexts and highlights the functional redundancy often exhibited by enzymes involved in lipid metabolism.
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Affiliation(s)
- Ran Wang
- Center for Environmental Health Sciences, Department of Basic Sciences, College of Veterinary Medicine, Mississippi State University , University, Mississippi 39762, United States
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Abstract
Young-onset dementia is a neurologic syndrome that affects behavior and cognition of patients younger than 65 years of age. Although frequently misdiagnosed, a systematic approach, reliant upon attainment of a detailed medical history, a collateral history, neuropsychological testing, laboratory studies, and neuroimaging, may facilitate earlier and more accurate diagnosis with subsequent intervention. The differential diagnosis of young-onset dementia is extensive and includes early-onset forms of adult neurodegenerative conditions including Alzheimer's disease, vascular dementia, frontotemporal dementia, Lewy body dementias, Huntington's disease, and prion disease. Late-onset forms of childhood neurodegenerative conditions may also present as young-onset dementia and include mitochondrial disorders, lysosomal storage disorders, and leukodystrophies. Potentially reversible etiologies including inflammatory disorders, infectious diseases, toxic/metabolic abnormalities, transient epileptic amnesia, obstructive sleep apnea, and normal pressure hydrocephalus also represent important differential diagnostic considerations in young-onset dementia. This review will present etiologies, diagnostic strategies, and options for management of young-onset dementia with comprehensive summary tables for clinical reference.
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Affiliation(s)
- Dulanji K Kuruppu
- Indiana University School of Medicine, 5457 Fieldhurst Lane, Plainfield, IN 46168, Telephone: 317-450-8801
| | - Brandy R Matthews
- Department of Neurology, Indiana University School of Medicine, 355 W. 16th Street, Suite 4700, Indianapolis, IN 46202, Telephone: 317-944-4000, Fax: 317-963-7559
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Warnock A, Tan L, Li C, An Haack K, Narayan SB, Bennett MJ. Amlodipine prevents apoptotic cell death by correction of elevated intracellular calcium in a primary neuronal model of Batten disease (CLN3 disease). Biochem Biophys Res Commun 2013; 436:645-9. [PMID: 23769828 DOI: 10.1016/j.bbrc.2013.04.113] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 04/27/2013] [Indexed: 01/06/2023]
Abstract
CLN3 disease (Spielmeyer-Vogt-Sjogren-Batten disease) is a severe pediatric neurodegenerative disorder for which there is currently no effective treatment. The disease is characterized by progressive neuronal death, which may be triggered by abnormal intracellular calcium levels leading to neuronal apoptosis. Previously, we demonstrated reversal of the calcium effect in a neuroblastoma cell line using amlodipine and other calcium channel antagonists. In the present studies, we developed a CLN3 siRNA-inhibited primary rat neuron model to further study etoposide-induced calcium changes and apoptosis in CLN3 disease followed by recovery experiments with amlodipine. Our results show that intracellular calcium is significantly elevated in siRNA-inhibited cortical neurons after potassium chloride-induced depolarization. We were also able to show that amlodipine, a predominantly L-type dihydropyrimidine calcium channel antagonist can reverse the aberrant calcium elevations in this model of the disease. We performed an in situ TUNEL assay following etoposide-exposure to siRNA inhibited primary neurons, and apoptotic nuclei were detected providing additional evidence that increased neuronal apoptosis is associated with increased calcium levels. Amlodipine also reduced the absolute number of apoptotic cells in this experimental model.
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Affiliation(s)
- Ashley Warnock
- Department of Pathology & Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
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Mahmood F, Fu S, Cooke J, Wilson SW, Cooper JD, Russell C. A zebrafish model of CLN2 disease is deficient in tripeptidyl peptidase 1 and displays progressive neurodegeneration accompanied by a reduction in proliferation. Brain 2013; 136:1488-507. [DOI: 10.1093/brain/awt043] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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Pérez-Poyato MS, Marfa MP, Abizanda IF, Rodriguez-Revenga L, Sánchez VC, González MJM, Puñal JE, Pérez AV, González MMG, Bermejo AM, Hernández EM, Rosell MJC, Gort L, Milá M. Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. J Child Neurol 2013; 28:470-8. [PMID: 22832778 DOI: 10.1177/0883073812448459] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Late infantile neuronal ceroid lipofuscinosis (Jansky-Bielchowsky disease) is a rare disease caused by mutations in the CLN2 gene. The authors report the clinical outcome and correlate with genotype in 12 Spanish patients with this disease. Psychomotor regression, epilepsy, and other clinical symptoms/signs were assessed. Age at onset of clinical symptoms ranged from 18 months to 3.7 years, and they included delayed speech and simple febrile seizures followed by epilepsy. Partial seizures and myoclonic jerks occurred at an earlier age (median 3.4 and 3.7 years, respectively) than ataxia and cognitive decline (median 4 years). Clinical regression was initiated by loss of sentences (median 3.7 years) followed by loss of walking ability and absence of language (median 4.5 years). Patients showed blindness and lost sitting ability at similar age (median 5 years). The authors report 4 novel mutations in the CLN2 gene. This study provides detailed information about the natural history of this disease.
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Affiliation(s)
- María S Pérez-Poyato
- Department of Pediatric Neurology, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
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Abstract
Neuronal ceroid lipofuscinoses (NCL) represent a group of autosomal recessive neurodegenerative disorders, presenting with myoclonic epilepsy, psychomotor delay, progressive loss of vision, and early death. Four main clinical forms have been delineated (infantile, late infantile, juvenile, and adult), but many other variants have also been described. At least 14 genetically distinct NCL, designated CLN1 to CLN14, are presently known.The identification of the deficient protein and/or the genetic defect is required for a specific diagnosis, which is necessary for a reliable genetic counseling in at-risk families.
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Ueda T, Narushima E, Ishida E, Akiguchi I. Neuronal ceroid lipofuscinosis with early-onset dementia and periventricular leukoencephalopathy in which a skin biopsy was diagnostically useful. Intern Med 2013; 52:2271-4. [PMID: 24088765 DOI: 10.2169/internalmedicine.52.0505] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Neuronal ceroid lipofuscinosis (NCL) is a rare disease with onset typically during childhood; however, that developing during adulthood can lead to early-onset dementia. We report a 54-year-old man whose onset coincided with speech impairment, amnesia and dyscalculia. On brain MRI, marked diffuse leukoencephalopathy with periventricular predominance was observed. On a skin biopsy, characteristic fingerprint images were noted, and the patient was diagnosed with NCL. The differential diagnosis of cognitive impairment with leukoencephalopathy is wide ranging; however, when marked symmetrical periventricular-predominant leukoencephalopathy is prevalent and no peripheral neuropathy or gait disorders are evident, a diagnosis of NCL should be suspected and a skin biopsy should be performed.
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Affiliation(s)
- Takeshi Ueda
- Rakuwakai Marutamachi Hospital, Emergency Medicine and General Internal Medicine, Japan
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Paniagua Bravo A, Forkert ND, Schulz A, Löbel U, Fiehler J, Ding X, Sedlacik J, Rosenkranz M, Goebell E. Quantitative T2 Measurements in Juvenile and Late Infantile Neuronal Ceroid Lipofuscinosis. Clin Neuroradiol 2012; 23:189-96. [DOI: 10.1007/s00062-012-0189-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 11/29/2012] [Indexed: 11/29/2022]
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In a model of Batten disease, palmitoyl protein thioesterase-1 deficiency is associated with brown adipose tissue and thermoregulation abnormalities. PLoS One 2012; 7:e48733. [PMID: 23139814 PMCID: PMC3490854 DOI: 10.1371/journal.pone.0048733] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Accepted: 09/28/2012] [Indexed: 11/19/2022] Open
Abstract
Infantile neuronal ceroid lipofuscinosis (INCL) is a fatal neurodegenerative disorder caused by a deficiency of palmitoyl-protein thioesterase-1 (PPT1). We have previously shown that children with INCL have increased risk of hypothermia during anesthesia and that PPT1-deficiency in mice is associated with disruption of adaptive energy metabolism, downregulation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and mitochondrial dysfunction. Here we hypothesized that Ppt1-knockout mice, a well-studied model of INCL that shows many of the neurologic manifestations of the disease, would recapitulate the thermoregulation impairment observed in children with INCL. We also hypothesized that when exposed to cold, Ppt1-knockout mice would be unable to maintain body temperature as in mice thermogenesis requires upregulation of Pgc-1α and uncoupling protein 1 (Ucp-1) in brown adipose tissue. We found that the Ppt1-KO mice had lower basal body temperature as they aged and developed hypothermia during cold exposure. Surprisingly, this inability to maintain body temperature during cold exposure in Ppt1-KO mice was associated with an adequate upregulation of Pgc-1α and Ucp-1 but with lower levels of sympathetic neurotransmitters in brown adipose tissue. In addition, during baseline conditions, brown adipose tissue of Ppt1-KO mice had less vacuolization (lipid droplets) compared to wild-type animals. After cold stress, wild-type animals had significant decreases whereas Ppt1-KO had insignificant changes in lipid droplets compared with baseline measurements, thus suggesting that Ppt1-KO had less lipolysis in response to cold stress. These results uncover a previously unknown phenotype associated with PPT1 deficiency, that of altered thermoregulation, which is associated with impaired lipolysis and neurotransmitter release to brown adipose tissue during cold exposure. These findings suggest that INCL should be added to the list of neurodegenerative diseases that are linked to alterations in peripheral metabolic processes. In addition, extrapolating these findings clinically, impaired thermoregulation and hypothermia are potential risks in patients with INCL.
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Kovács AD, Saje A, Wong A, Ramji S, Cooper JD, Pearce DA. Age-dependent therapeutic effect of memantine in a mouse model of juvenile Batten disease. Neuropharmacology 2012; 63:769-75. [PMID: 22683643 DOI: 10.1016/j.neuropharm.2012.05.040] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Revised: 05/11/2012] [Accepted: 05/25/2012] [Indexed: 01/08/2023]
Abstract
Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3(Δex1-6)) mouse model recapitulates several features of the human disorder. Cln3(Δex1-6) mice, similarly to juvenile Batten disease patients, have a motor coordination deficit detectable as early as postnatal day 14. Previous studies demonstrated that acute attenuation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7-month-old Cln3(Δex1-6) mice results in improvement in motor coordination. Here we show that acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the impaired motor coordination of one-month-old Cln3(Δex1-6) mice. At a later stage of the disease, in 6-7-month-old Cln3(Δex1-6) mice, memantine induced a delayed but extended (8 days) improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. An age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3(Δex1-6) mice had no beneficial effect on motor coordination. Moreover, repeated treatments did not impact microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease.
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Affiliation(s)
- Attila D Kovács
- Sanford Children's Health Research Center, Sanford Research/USD, Sioux Falls, SD 57104, USA
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Ferlazzo E, Gasparini S, Pasquinelli G, Labate A, Gambardella A, Sofia V, Cianci V, Branca D, Quattrone A, Aguglia U. Usefulness of rectal biopsy for the diagnosis of Kufs disease: a controlled study and review of the literature. Eur J Neurol 2012; 19:1331-6. [PMID: 22568672 DOI: 10.1111/j.1468-1331.2012.03748.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Accepted: 03/30/2012] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND PURPOSE Rectal biopsy is usually performed for in vivo diagnosis of Kufs disease (KD). We evaluated the usefulness of rectal biopsy in the diagnosis of such condition by comparing ultrastructural data of patients with suspicion of KD with those of control subjects. Furthermore, we reviewed literature data concerning the value of such a diagnostic procedure in the diagnosis of KD. METHODS Sixty-five subjects were enrolled and underwent rectal biopsy. Of these, 13 had a clinical picture in keeping with KD, whereas 52, affected by Irritable Bowel Syndrome, constituted the control group. RESULTS Ultrastructural analysis evidenced fingerprint (FP) inclusions in 12 subjects, 4/13 with suspicion of KD and 8/52 controls. In patients, FPs were mainly located in vascular smooth muscle cells (VSMC) while in controls they were mostly found in pericytes and VSMC. No FPs were found in one patient with genetically confirmed KD. In literature, we identified 14 KD patients who underwent rectal biopsy. In most reports, ultrastructural features were not systematically analyzed or described. CONCLUSIONS Fingerprints are the most common ultrastructural finding in rectal biopsy in patients with suspicion of KD. However, their presence in pericytes and VSMC is not specific for KD because they may be found in controls subjects. Our literature review revealed that data on the value of rectal biopsy in the diagnosis of KD are scarce. In light of these findings, the relevance of rectal biopsy in such condition should be re-evaluated.
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Affiliation(s)
- E Ferlazzo
- Institute of Neurology, Magna Graecia University, Catanzaro, Italy
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Dhamija R, Patterson MC, Wirrell EC. Epilepsy in children--when should we think neurometabolic disease? J Child Neurol 2012; 27:663-71. [PMID: 22378665 DOI: 10.1177/0883073811435829] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Seizures are often the first manifestation of central nervous system dysfunction and are common in many inborn errors of metabolism, especially in neonates, infants, and children. A high index of suspicion is required to diagnose inborn errors of metabolism as the cause of seizures. It is also important to recognize these metabolic disorders early, as specific disease-modifying treatments are available for some with favorable long-term outcomes. This review discusses the classification of metabolic disorders as a cause of seizures based on pathogenesis and age and proposes a tiered approach for cost-effective diagnosis of metabolic disorders.
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Affiliation(s)
- Radhika Dhamija
- Division of Child and Adolescent Neurology, Mayo Clinic Children's Center, Rochester, MN 55905, USA
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Thelen M, Daμμe M, Schweizer M, Hagel C, Wong AM, Cooper JD, Braulke T, Galliciotti G. Disruption of the autophagy-lysosome pathway is involved in neuropathology of the nclf mouse model of neuronal ceroid lipofuscinosis. PLoS One 2012; 7:e35493. [PMID: 22536393 PMCID: PMC3335005 DOI: 10.1371/journal.pone.0035493] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2012] [Accepted: 03/16/2012] [Indexed: 11/18/2022] Open
Abstract
Variant late-infantile neuronal ceroid lipofuscinosis, a fatal lysosomal storage disorder accompanied by regional atrophy and pronounced neuron loss in the brain, is caused by mutations in the CLN6 gene. CLN6 is a non-glycosylated endoplasmic reticulum (ER)-resident membrane protein of unknown function. To investigate mechanisms contributing to neurodegeneration in CLN6 disease we examined the nclf mouse, a naturally occurring model of the human CLN6 disease. Prominent autofluorescent and electron-dense lysosomal storage material was found in cerebellar Purkinje cells, thalamus, hippocampus, olfactory bulb and in cortical layer II to V. Another prominent early feature of nclf pathogenesis was the localized astrocytosis that was evident in many brain regions and the more widespread microgliosis. Expression analysis of mutant Cln6 found in nclf mice demonstrated synthesis of a truncated protein with a reduced half-life. Whereas the rapid degradation of the mutant Cln6 protein can be inhibited by proteasomal inhibitors, there was no evidence for ER stress or activation of the unfolded protein response in various brain areas during postnatal development. Age-dependent increases in LC3-II, ubiquitinated proteins, and neuronal p62-positive aggregates were observed, indicating a disruption of the autophagy-lysosome degradation pathway of proteins in brains of nclf mice, most likely due to defective fusion between autophagosomes and lysosomes. These data suggest that proteasomal degradation of mutant Cln6 is sufficient to prevent the accumulation of misfolded Cln6 protein, whereas lysosomal dysfunction impairs constitutive autophagy promoting neurodegeneration.
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Affiliation(s)
- Melanie Thelen
- Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus Daμμe
- Department of Biochemistry 1, University Bielefeld, Bielefeld, Germany
| | - Michaela Schweizer
- Center for Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Hagel
- Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrew M.S. Wong
- Department of Neuroscience and Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Kinǵs College London, Institute of Psychiatry, London, United Kingdom
| | - Jonathan D. Cooper
- Department of Neuroscience and Centre for the Cellular Basis of Behaviour, MRC Centre for Neurodegeneration Research, Kinǵs College London, Institute of Psychiatry, London, United Kingdom
| | - Thomas Braulke
- Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Giovanna Galliciotti
- Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- * E-mail:
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The role of ceroid lipofuscinosis neuronal protein 5 (CLN5) in endosomal sorting. Mol Cell Biol 2012; 32:1855-66. [PMID: 22431521 DOI: 10.1128/mcb.06726-11] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Mutations in the gene encoding CLN5 are the cause of Finnish variant late infantile Neuronal Ceroid Lipofuscinosis (NCL), and the gene encoding CLN5 is 1 of 10 genes (encoding CLN1 to CLN9 and cathepsin D) whose germ line mutations result in a group of recessive disorders of childhood. Although CLN5 localizes to the lysosomal compartment, its function remains unknown. We have uncovered an interaction between CLN5 and sortilin, the lysosomal sorting receptor. However, CLN5, unlike prosaposin, does not require sortilin to localize to the lysosomal compartment. We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component). In addition, we show that the retromer recruitment machinery is also affected by CLN5 depletion, as we found less loaded Rab7, which is required to recruit retromer. Taken together, our results support a role for CLN5 in controlling the itinerary of the lysosomal sorting receptors by regulating retromer recruitment at the endosome.
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Saha A, Sarkar C, Singh SP, Zhang Z, Munasinghe J, Peng S, Chandra G, Kong E, Mukherjee AB. The blood-brain barrier is disrupted in a mouse model of infantile neuronal ceroid lipofuscinosis: amelioration by resveratrol. Hum Mol Genet 2012; 21:2233-44. [PMID: 22331300 DOI: 10.1093/hmg/dds038] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Disruption of the blood-brain barrier (BBB) is a serious complication frequently encountered in neurodegenerative disorders. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating childhood neurodegenerative lysosomal storage disorder caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. It remains unclear whether BBB is disrupted in INCL and if so, what might be the molecular mechanism(s) of this complication. We previously reported that the Ppt1-knockout (Ppt1-KO) mice that mimic INCL manifest high levels of oxidative stress and neuroinflammation. Recently, it has been reported that CD4(+) T-helper 17 (T(H)17) lymphocytes may mediate BBB disruption and neuroinflammation, although the precise molecular mechanism(s) remain unclear. We sought to determine: (i) whether the BBB is disrupted in Ppt1-KO mice, (ii) if so, do T(H)17-lymphocytes underlie this complication, and (iii) how might T(H)17 lymphocytes breach the BBB. Here, we report that the BBB is disrupted in Ppt1-KO mice and that T(H)17 lymphocytes producing IL-17A mediate disruption of the BBB by stimulating production of matrix metalloproteinases (MMPs), which degrade the tight junction proteins essential for maintaining BBB integrity. Importantly, dietary supplementation of resveratrol (RSV), a naturally occurring antioxidant/anti-inflammatory polyphenol, markedly reduced the levels of T(H)17 cells, IL-17A and MMPs, and elevated the levels of tight junction proteins, which improved the BBB integrity in Ppt1-KO mice. Intriguingly, we found that RSV suppressed the differentiation of CD4(+) T lymphocytes to IL-17A-positive T(H)17 cells. Our findings uncover a mechanism by which T(H)17 lymphocytes mediate BBB disruption and suggest that small molecules such as RSV that suppress T(H)17 differentiation are therapeutic targets for neurodegenerative disorders such as INCL.
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Affiliation(s)
- Arjun Saha
- Section on Developmental Genetics, Program on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD 20892-1830, USA
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Munasinghe J, Zhang Z, Kong E, Heffer A, Mukherjee AB. Evaluation of neurodegeneration in a mouse model of infantile batten disease by magnetic resonance imaging and magnetic resonance spectroscopy. NEURODEGENER DIS 2012; 9:159-69. [PMID: 22327870 DOI: 10.1159/000334838] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 10/31/2011] [Indexed: 11/19/2022] Open
Abstract
Neuronal ceroid lipofuscinoses (NCLs) represent a group of common hereditary childhood neurodegenerative storage disorders that have no effective treatment. Mutations in eight different genes cause various forms of NCLs. Infantile NCL (INCL), the most lethal disease, is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. The availability of Ppt1-knockout (Ppt1-KO) mice, which recapitulate virtually all clinical and pathological features of INCL, provides an opportunity to test the effectiveness of novel therapeutic strategies in vivo. However, such studies will require noninvasive methods that can be used to perform serial evaluations of the same animal receiving an experimental therapy. Thus, the development of noninvasive method(s) of evaluation is urgently needed. Here, we report our evaluation of the progression of neurodegeneration in Ppt1-KO mice starting at 3 months of age by MRI and MR spectroscopy (MRS) and repeating these tests using the same mice at 4, 5 and 6 months of age. Our results showed progressive cerebral atrophy, which was associated with histological loss of neuronal content and increase in astroglia. Remarkably, while the brain volumes in Ppt1-KO mice progressively declined with advancing age, the MRS signals, which were significantly lower than those of their wild-type littermates, remained virtually unchanged from 3 to 6 months of age. In addition, our results also showed an abnormality in cerebral blood flow in these mice, which showed progression with age. Our findings provide methods to serially examine the brains of mouse models of neurodegenerative diseases (e.g. Ppt1-KO mice) using noninvasive and nonlethal procedures such as MRI and MRS. These methods may be useful in studies to understand the progression of neuropathology in animal models of neurodegenerative diseases as they allow repeated evaluations of the same animal in which experimental therapies are tested.
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Affiliation(s)
- Jeeva Munasinghe
- In Vivo NMR Center-HNQ2-3, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1830, USA.
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Bigini P, Milanese M, Gardoni F, Longhi A, Bonifacino T, Barbera S, Fumagalli E, Di Luca M, Mennini T, Bonanno G. Increased [3H]D-aspartate release and changes in glutamate receptor expression in the hippocampus of the mnd mouse. J Neurosci Res 2012; 90:1148-58. [DOI: 10.1002/jnr.22831] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 10/20/2011] [Accepted: 10/21/2011] [Indexed: 11/10/2022]
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Kwon JM, Adams H, Rothberg PG, Augustine EF, Marshall FJ, Deblieck EA, Vierhile A, Beck CA, Newhouse NJ, Cialone J, Levy E, Ramirez-Montealegre D, Dure LS, Rose KR, Mink JW. Quantifying physical decline in juvenile neuronal ceroid lipofuscinosis (Batten disease). Neurology 2011; 77:1801-7. [PMID: 22013180 PMCID: PMC3233207 DOI: 10.1212/wnl.0b013e318237f649] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2011] [Accepted: 05/13/2011] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE To use the Unified Batten Disease Rating Scale (UBDRS) to measure the rate of decline in physical and functional capability domains in patients with juvenile neuronal ceroid lipofuscinosis (JNCL) or Batten disease, a neurodegenerative lysosomal storage disorder. We have evaluated the UBDRS in subjects with JNCL since 2002; during that time, the scale has been refined to improve reliability and validity. Now that therapies are being proposed to prevent, slow, or reverse the course of JNCL, the UBDRS will play an important role in quantitatively assessing clinical outcomes in research trials. METHODS We administered the UBDRS to 82 subjects with JNCL genetically confirmed by CLN3 mutational analysis. Forty-four subjects were seen for more than one annual visit. From these data, the rate of physical impairment over time was quantified using multivariate linear regression and repeated-measures analysis. RESULTS The UBDRS Physical Impairment subscale shows worsening over time that proceeds at a quantifiable linear rate in the years following initial onset of clinical symptoms. This deterioration correlates with functional capability and is not influenced by CLN3 genotype. CONCLUSION The UBDRS is a reliable and valid instrument that measures clinical progression in JNCL. Our data support the use of the UBDRS to quantify the rate of progression of physical impairment in subjects with JNCL in clinical trials.
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Affiliation(s)
- J M Kwon
- University of Rochester, Rochester, NY, USA.
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