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Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss

Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases mostly affecting cerebellar Purkinje cells caused by a wide variety of different mutations. One subtype, SCA14, is caused by mutations of Protein Kinase C gamma (PKCγ), the dominant PKC isoform present in Purkinje ce...

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Autores principales: Kapfhammer, Josef P., Shimobayashi, Etsuko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323145/
https://www.ncbi.nlm.nih.gov/pubmed/37426070
http://dx.doi.org/10.3389/fnmol.2023.1182431
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author Kapfhammer, Josef P.
Shimobayashi, Etsuko
author_facet Kapfhammer, Josef P.
Shimobayashi, Etsuko
author_sort Kapfhammer, Josef P.
collection PubMed
description Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases mostly affecting cerebellar Purkinje cells caused by a wide variety of different mutations. One subtype, SCA14, is caused by mutations of Protein Kinase C gamma (PKCγ), the dominant PKC isoform present in Purkinje cells. Mutations in the pathway in which PKCγ is active, i.e., in the regulation of calcium levels and calcium signaling in Purkinje cells, are the cause of several other variants of SCA. In SCA14, many of the observed mutations in the PKCγ gene were shown to increase the basal activity of PKCγ, raising the possibility that increased activity of PKCγ might be the cause of most forms of SCA14 and might also be involved in the pathogenesis of SCA in related subtypes. In this viewpoint and review article we will discuss the evidence for and against such a major role of PKCγ basal activity and will suggest a hypothesis of how PKCγ activity and the calcium signaling pathway may be involved in the pathogenesis of SCAs despite the different and sometimes opposing effects of mutations affecting these pathways. We will then widen the scope and propose a concept of SCA pathogenesis which is not primarily driven by cell death and loss of Purkinje cells but rather by dysfunction of Purkinje cells which are still present and alive in the cerebellum.
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spelling pubmed-103231452023-07-07 Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss Kapfhammer, Josef P. Shimobayashi, Etsuko Front Mol Neurosci Molecular Neuroscience Spinocerebellar ataxias (SCAs) are a group of hereditary neurodegenerative diseases mostly affecting cerebellar Purkinje cells caused by a wide variety of different mutations. One subtype, SCA14, is caused by mutations of Protein Kinase C gamma (PKCγ), the dominant PKC isoform present in Purkinje cells. Mutations in the pathway in which PKCγ is active, i.e., in the regulation of calcium levels and calcium signaling in Purkinje cells, are the cause of several other variants of SCA. In SCA14, many of the observed mutations in the PKCγ gene were shown to increase the basal activity of PKCγ, raising the possibility that increased activity of PKCγ might be the cause of most forms of SCA14 and might also be involved in the pathogenesis of SCA in related subtypes. In this viewpoint and review article we will discuss the evidence for and against such a major role of PKCγ basal activity and will suggest a hypothesis of how PKCγ activity and the calcium signaling pathway may be involved in the pathogenesis of SCAs despite the different and sometimes opposing effects of mutations affecting these pathways. We will then widen the scope and propose a concept of SCA pathogenesis which is not primarily driven by cell death and loss of Purkinje cells but rather by dysfunction of Purkinje cells which are still present and alive in the cerebellum. Frontiers Media S.A. 2023-06-22 /pmc/articles/PMC10323145/ /pubmed/37426070 http://dx.doi.org/10.3389/fnmol.2023.1182431 Text en Copyright © 2023 Kapfhammer and Shimobayashi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Kapfhammer, Josef P.
Shimobayashi, Etsuko
Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title_full Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title_fullStr Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title_full_unstemmed Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title_short Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss
title_sort viewpoint: spinocerebellar ataxias as diseases of purkinje cell dysfunction rather than purkinje cell loss
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323145/
https://www.ncbi.nlm.nih.gov/pubmed/37426070
http://dx.doi.org/10.3389/fnmol.2023.1182431
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