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Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias

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Abstract

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of more than 30 autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by progressive ataxia and cerebellar atrophy. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, 17 different gene loci have so far been implicated as culprits in these SCAs. It is not currently understood how mutations in these 17 proteins lead to the cerebellar atrophy and ataxia. Several pathogenic mechanisms have been studied in SCAs but there is yet to be a promising target for successful treatment of SCAs. Emerging research suggests that a fundamental cellular signaling pathway is disrupted by a majority of these mutated genes, which could explain the characteristic death of Purkinje cells, cerebellar atrophy, and ataxia that occur in many SCAs. We propose that mutations in SCA genes cause disruptions in multiple cellular pathways but the characteristic SCA pathogenesis does not begin until calcium signaling pathways are disrupted in cerebellar Purkinje cells either as a result of an excitotoxic increase or a compensatory suppression of calcium signaling. We argue that disruptions in Purkinje cell calcium signaling lead to initial cerebellar dysfunction and ataxic sympoms and eventually proceed to Purkinje cell death. Here, we discuss a calcium hypothesis of Purkinje cell neurodegeneration in SCAs by primarily focusing on an example of spinocerebellar ataxia 2 (SCA2). We will also present evidence linking deranged calcium signaling to the pathogenesis of other SCAs (SCA1, 3, 5, 6, 14, 15/16) that lead to significant Purkinje cell dysfunction and loss in patients.

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Acknowledgements

A.K. is a Howard Hughes Medical Institute Med into Grad Scholar. I.B. is a holder of Carla Cocke Francis Professorship in Alzheimer's Research and supported by the McKnight Neuroscience of Brain Disorders Award. The work on SCA2 and SCA3 was supported by the National Organization for Rare Disorders, National Ataxia Foundation, Ataxia MJD Research Project, and the National Institutes of Health grants R01NS38082 and R01NS056224.

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    Adebimpe Kasumu & Ilya Bezprozvanny

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Kasumu, A., Bezprozvanny, I. Deranged Calcium Signaling in Purkinje Cells and Pathogenesis in Spinocerebellar Ataxia 2 (SCA2) and Other Ataxias. Cerebellum 11, 630–639 (2012). https://doi.org/10.1007/s12311-010-0182-9

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