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Regulation of Ataxin-1 Phosphorylation and Its Impact on Biology

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Ataxin-1 protein expression is found in the cytoplasm and nucleus of Purkinje cells, the primary site of spinocerebellar ataxia type 1 (SCA1). Phosphorylation at S776 occurs in the cytoplasm and stabilizes the protein through interaction with 14-3-3, allowing it to translocate into the nucleus where disease is initiated. Phosphorylation and stabilization are enhanced when the polyglutamine expansion is present. In this chapter, we present a model of neurodegeneration in SCA1 initiated through phosphorylation at S776 by cAMP-dependent protein kinase (PKA) and enhanced by the presence of the polyglutamine expansion. The biological methods used to uncover SCA1 pathogenesis and phosphorylation at S776 are described.
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