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 (PKC & gamma;), the dominant PKC isoform present in Purkinje cells. Mutations in the pathway in which PKC & gamma; 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 PKC & gamma; gene were shown to increase the basal activity of PKC & gamma;, raising the possibility that increased activity of PKC & gamma; 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 PKC & gamma; basal activity and will suggest a hypothesis of how PKC & gamma; 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.

Automated summary

Spinocerebellar ataxias (SCAs) are hereditary neurodegenerative diseases characterized by mutations affecting cerebellar Purkinje cells. One subtype, SCA14, is caused by mutations in the Protein Kinase C gamma (PKCγ) gene, which leads to increased basal activity of PKCγ. This increased activity may be the cause of most forms of SCA14 and could be involved in the pathogenesis of related subtypes. Additionally, the pathogenesis of SCAs may be driven by dysfunction of Purkinje cells rather than cell death and loss.