Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ataxin-1. Previous work has shown that the subcellular deposition and localization of mutant ataxin-1 plays a critical role in the pathogenesis of SCA1. A key player in numerous cell-signaling pathways, many associated with neurodegeneration, is the enzyme glycogen synthase kinase 3 (GSK3). Our results indicate that serines 776 and 780 of ataxin-1 play a role in the subcellular localization of this protein, perhaps via their phosphorylation by GSK3b. Thus, the goal of the research described below is to determine whether cell-signaling pathways acting through these serines of ataxin-1 are biologically relevant GSK3b has recently emerged as a key target in drug discovery. If it proves to be the case that SCA1 pathogenesis is associated with increased levels of GSK3b activity, GSK3b inhibitors might have a therapeutic role in SCA1.
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