ArticleActa neuropathologica communications2018
Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation.
Article in Acta neuropathologica communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 51 citations in OpenAlex.
- Rare 19q13.42 duplication encompassingTranslational pediatrics · 2026Article
- Sex-specific disruptions in PKCγ signaling in a mouse model of spinocerebellar ataxia type 14.JCI insight · 2026Article
- Familial SCA14: A case report with review.Experimental and therapeutic medicine · 2026Article
- Purkinje cell intrinsic activity shapes cerebellar development and function.Nature communications · 2026Article
- Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome.Nature communications · 2026Article
- PKCγ-mediated Phosphorylation of Mtss1 Regulates the Dendritic Outgrowth and Spine Development of Cerebellar Purkinje Cells.Molecular neurobiology · 2025Article
- Roots of Progress: Uncovering Cerebellar Ataxias Using iPSC Models.Biomedicines · 2025Review
- Genome-wide methylome-based molecular pathologies associated with depression and suicide.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Advancements in Protein Kinase Inhibitors: From Discovery to Clinical Applications.Research (Washington, D.C.) · 2025Review
- A selective review of inhibitors of protein kinase C gamma: a neuroplasticity-related common pathway for psychiatric illness.Frontiers in drug delivery · 2024Review
- Non-synonymous SNPs variants of PRKCG and its association with oncogenes predispose to hepatocellular carcinoma.Cancer cell international · 2023Article
- Spinocerebellar ataxia type 14 (SCA14) in an Argentinian family: a case report.Journal of medical case reports · 2023Article
- Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss.Frontiers in molecular neuroscience · 2023Review
- Novel mutation in exon11 ofFrontiers in genetics · 2023Article
- Mutations in protein kinase Cγ promote spinocerebellar ataxia type 14 by impairing kinase autoinhibition.Science signaling · 2022Article
- Consensus Paper: Strengths and Weaknesses of Animal Models of Spinocerebellar Ataxias and Their Clinical Implications.Cerebellum (London, England) · 2022Article
- Episodic ataxia and severe infantile phenotype in spinocerebellar ataxia type 14: expansion of the phenotype and novel mutations.Journal of neurology · 2022Article
- Optimal Formula of Angelica sinensis Ameliorates Memory Deficits in β-amyloid Protein-induced Alzheimer's Disease Rat Model.Current medical science · 2022Article
- Human Induced Pluripotent Stem Cell-Based Modelling of Spinocerebellar Ataxias.Stem cell reviews and reports · 2022Review
- Patient-Specific iPSCs-Based Models of Neurodegenerative Diseases: Focus on Aberrant Calcium Signaling.International journal of molecular sciences · 2022Review
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Authors and funding
10 authors at 4 institutions in 1 country.
Funding
Abstract
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.
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