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Infant onset spinocerebellar ataxia type 13 mutation leads to developmental and rapid degenerative phenotypes related to hyperexcitability in Purkinje cells


Spinocerebellar ataxia type 13 (SCA13) is an autosomal dominant neurodegenerative disease that leads to cerebellar ataxia and atrophy. It can exist in both adult and infant onset forms, caused by different mutations in voltage-gated K+ channel 3.3 (Kv3.3). The three causative mutations are adult onset R3H, infant onset R4H, and infant onset FL. The adult onset R3H and infant onset R4H mutations are located in the voltage sensor and lead to differential defects in channel function, which then lead to differential changes in Purkinje cell excitability. The adult onset mutation leads to latent hypoexcitability, whereas the infant onset mutation leads to rapid hyperexcitability followed by silence. We hypothesized that differential changes in Purkinje cell excitability caused by each mutation lead to differential changes in Purkinje cell development and survival and that reducing the hyperexcitability in Purkinje cells expressing the infant onset mutation would rescue the degenerative phenotype. We first confirmed the expression of Nav1.6 and Kv3.3 channels, both involved in mediating spontaneous tonic firing in mammalian Purkinje cells. It was necessary to confirm that this regulation was conserved in zebrafish, and that endogenous Kv3.3 was expressed in order to use zebrafish as a model for SCA13. The infant onset mutation leads to developmental abnormalities in Purkinje cells, as well as rapid degeneration and cell loss due to apoptotic cell death, typically by 6 dpf. The adult onset mutation did not alter Purkinje cell development or survival. When zebrafish expressing the infant onset mutation were treated with the SK2 channel agonist NS13001 to reduce hyperexcitability, the frequency of mutant cells significantly increased compared to DMSO controls, however, the degenerative phenotype was not rescued. This suggests a possible effect on Purkinje cell viability. We cannot rule out the role of hyperexcitability in degeneration because the efficacy of the drug was unclear. Previously, increased intracellular Ca2+ was observed in Purkinje cells expressing the infant onset mutation and may be implicated in a variety of cellular stress responses, such as mitochondrial dysfunction and/or ER stress, that could lead to apoptosis. Altered neuronal excitability and increased Ca2+ concentration have been observed in several neurodegenerative diseases and further investigating SCA13 will provide invaluable insight to our understanding of the mechanisms behind neurodegeneration.

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