Spinocerebellar Ataxia type 1 (SCAl) is an autosomal dominant neurodegenerative disease caused by an expanded polyglutamine tract in ataxin-1. Phosphorylation of ataxin-1 at S776 is an important mediator of ataxin-1 turnover and SCAl pathogenesis. Mice expressing a SCA1 transgene are behaviorally indistinguishable from wild-type mice. Pathologically, these mice develop a very mild SCAl phenotype late in life. On a molecular level, S776 has been shown to mediate the interaction between ataxin-1 and 14-3-3. 14-3-3 binding to ataxin-1 stabilizes the ataxin-1 protein. A cell-based assay can also be used to identify two signaling pathways important for regulating S776 phosphorylation. One pathway appears to work in a calcium-dependent manner to phosphorylate both mutant and wild-type ataxin-1. The second pathway is mutant specific and involves PI3K/AKT signaling. The discovery of S776 phosphorylation is an important regulator of ataxin-1 turnover, as well as the identification of two signaling pathways involved in this regulation opened up a new area to explore for therapeutic development in SCAl.
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