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...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-06-01
|
| Series: | Frontiers in Molecular Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1182431/full |
| _version_ | 1797797887954911232 |
|---|---|
| author | Josef P. Kapfhammer Etsuko Shimobayashi |
| author_facet | Josef P. Kapfhammer Etsuko Shimobayashi |
| author_sort | Josef P. Kapfhammer |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-13T03:55:09Z |
| format | Article |
| id | doaj.art-b41dccbe96344fb7bca4944a894cf1fc |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-03-13T03:55:09Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-b41dccbe96344fb7bca4944a894cf1fc2023-06-22T05:42:20ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992023-06-011610.3389/fnmol.2023.11824311182431Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell lossJosef P. KapfhammerEtsuko ShimobayashiSpinocerebellar 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.https://www.frontiersin.org/articles/10.3389/fnmol.2023.1182431/fullcerebellumneurodegenerative diseasesspinocerebellar ataxia (SCA)Purkinje cellProtein Kinase C gamma |
| spellingShingle | Josef P. Kapfhammer Etsuko Shimobayashi Viewpoint: spinocerebellar ataxias as diseases of Purkinje cell dysfunction rather than Purkinje cell loss Frontiers in Molecular Neuroscience cerebellum neurodegenerative diseases spinocerebellar ataxia (SCA) Purkinje cell Protein Kinase C gamma |
| 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 | cerebellum neurodegenerative diseases spinocerebellar ataxia (SCA) Purkinje cell Protein Kinase C gamma |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2023.1182431/full |
| work_keys_str_mv | AT josefpkapfhammer viewpointspinocerebellarataxiasasdiseasesofpurkinjecelldysfunctionratherthanpurkinjecellloss AT etsukoshimobayashi viewpointspinocerebellarataxiasasdiseasesofpurkinjecelldysfunctionratherthanpurkinjecellloss |