Mutation of the E6-AP ubiquitin ligase reduces nuclear inclusion frequencywhile accelerating polyglutamine-induced pathology in SCA1 mice

Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive nuclear inclusions (NI) that alter proteasome distribution in affected SCA1 patient neurons. H ere, we observed that ataxin-1 is degraded by the ubiquitin-proteasome path way. While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated eq ually well in vitro, the mutant form is three times more resistant to degra dation. Inhibiting proteasomal degradation promotes ataxin-1 aggregation in transfected cells. And in mice, Purkinje cells that express mutant ataxin- 1 but not a ubiquitin-protein ligase have significantly fewer Nls. Nonethel ess, the Purkinje cell pathology is markedly worse than that of SCA1 mice. Taken together, Nts are not necessary to induce neurodegeneration, but impa ired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 path ogenesis.