Modulation of ataxin-1 phosphorylation

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DESCRIPTION (provided by applicant): Spinocerebeltar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCAl-encoded protein ataxin-l. The subcellular localization and deposition of mutant ataxin-1 is a critical factor in the pathogenesis of SCA1. The mechanism(s) that control these events are not understood, however, phosphorylation is a mean to control protein localization and degradation. We sought to determine if ataxin-1 is phosphorylated, and have shown that serine 776 (S776) of both wild type and mutant ataxin-1 is phosphorylated in vivo and in vitro. Preventing phosphorylation of this residue by replacing it with alanine results in a mutant protein found in the nucleus that is not pathogenic. The goal of the research described below is to develop a cell culture based assay that can be used to screen a compound library for modulators of ataxin-1 serine 776 phosphorylation. Such a screen will identify new molecular tools to aid in elucidating the mechanism of SCA1 pathogenesis. Moreover, identified compounds will provide potential leads toward the development of a therapeutic treatment for SCA1. Lead compounds that have been validated will be used to begin preclinical testing using a mouse model of SCA1.