Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation
| Autor: | 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 |
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| Rok vydání: | 2018 |
| Předmět: |
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 |
| Zdroj: | Acta Neuropathologica Communications, Vol 6, Iss 1, Pp 1-14 (2018) Acta Neuropathologica Communications |
| ISSN: | 2051-5960 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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