Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited neurodegenerative disorders caused by a mutant protein with an expanded polyglutamine tract. Phosphorylation of ataxin‐1 (ATXN1) at serine 776 is implicated in SCA1 pathogenesis. Previous studies, utilizing transfected cell lines and a Drosophila photoreceptor model of SCA1, suggest that phosphorylating ATXN1 at S776 renders it less susceptible to degradation. This work also indicated that oncogene from AKR mouse thymoma (Akt) promotes the phosphorylation of ATXN1 at S776 and severity of neurodegeneration. Here, we examined the phosphorylation of ATXN1 at S776 in cerebellar Purkinje cells, a prominent site of pathology in SCA1. We found that while phosphorylation of S776 is associated with a stabilization of ATXN1 in Purkinje cells, inhibition of Akt either in vivo or in a cerebellar extract‐based phosphorylation assay did not decrease the phosphorylation of ATXN1‐S776. In contrast, immunodepletion and inhibition of cyclic AMP‐dependent protein kinase decreased phosphorylation of ATXN1‐S776. These results argue against Akt as the in vivo kinase that phosphorylates S776 of ATXN1 and suggest that cyclic AMP‐dependent protein kinase is the active ATXN1‐S776 kinase in the cerebellum.

Spinocerebellar Ataxia Type 1 (SCA1) is an autosomal dominant neurodegenerative disease caused by an expansion in the polyglutamine region of the ataxin‐1 (ATXN1) gene. Mutant expanded ATXN1 can be stabilized by phosphorylation at amino acid residue Ser776. In its stabilized form, ATXN1 aggregates in the nucleus and resists degradation, ultimately leading to cell death. However, in the presence of kinase inhibitors, mutant ATXN1 is rapidly degraded. This study examines the mechanism by which ATXN1 is readily degraded, using a Daoy cell model with expanded (82Q) and normal (30Q) ATXN1. Through manipulation of the proteasome, it was found that nuclear ATXN1, though ubiquitinated, is not degraded by the proteasome. Follow up studies will examine the effects of autophagy, a putative mechanism for rapid ATXN1 degradation, on aggregate clearance. Targeting cellular degradation mechanisms in SCA1 will provide a better understanding of the function of ATXN1 in its normal state and a starting point for future therapeutic studies.