Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation
| العنوان: | Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation |
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| المؤلفون: | Geraint Fuller, Maggie M. K. Wong, Jane Vowles, Lauren M Watson, Andrea H. Németh, Kevin Talbot, Esther B. E. Becker, Stephanie D. Hoekstra, Sally A. Cowley, Olaf Ansorge |
| المصدر: | Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-14 (2018) Acta Neuropathologica Communications |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Adult, Male, Cerebellum, Ataxia, Induced Pluripotent Stem Cells, Stem cells, Protein kinase C gamma, Biology, Models, Biological, Protein Aggregation, Pathological, lcsh:RC346-429, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Catalytic Domain, medicine, Humans, Spinocerebellar Ataxias, Neurodegeneration, Kinase activity, Induced pluripotent stem cell, lcsh:Neurology. Diseases of the nervous system, Protein Kinase C, C1 domain, Aged, Middle Aged, medicine.disease, PRKCG Gene, 3. Good health, Cell biology, Protein Transport, 030104 developmental biology, medicine.anatomical_structure, Purkinje cells, Mutation, Nerve Degeneration, Spinocerebellar ataxia, Female, Neurology (clinical), Autopsy, medicine.symptom, Protein Kinases, 030217 neurology & neurosurgery |
| الوصف: | Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration. SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCγ). Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood. Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCγ, H36R and H101Q. We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCγ in both patient iPSCs and cerebellum. PKCγ aggregates were not efficiently targeted for degradation. Moreover, mutant PKCγ was found to be hyper-activated, resulting in increased substrate phosphorylation. Together, our findings demonstrate that a combination of both, loss-of-function and gain-of-function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCγ. Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools. |
| وصف الملف: | application/pdf |
| تدمد: | 2051-5960 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::12f19b733411170256b52393434f8e9d https://pubmed.ncbi.nlm.nih.gov/30249303 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....12f19b733411170256b52393434f8e9d |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20515960 |
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