Evidence for proteasome involvement in polyglutamine disease: localizationto nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro

Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/M JD), is one of at least eight inherited neurodegenerative diseases caused b y expansion of a polyglutamine tract in the disease protein, Here we presen t two lines of evidence implicating the ubiquitin-proteasome pathway in SCA 3/MJD pathogenesis. First, studies of both human disease tissue and in vitr o models showed redistribution of the 26S proteasome complex into polygluta mine aggregates. In neurons from SCA3/MJD brain, the proteasome localized t o intranuclear inclusions containing the mutant protein, ataxin-3. In trans fected cells, the proteasome redistributed into inclusions formed by three expanded polyglutamine proteins: a pathologic ataxin-3 fragment, full-lengt h mutant ataxin-3 and an unrelated GFP-polyglutamine fusion protein. Inclus ion formation by the full-length mutant ataxin-3 required nuclear localizat ion of the protein and occurred within specific subnuclear structures recen tly implicated in the regulation of cell death, promyelocytic leukemia anti gen oncogenic domains, In a second set of experiments, inhibitors of the pr oteasome caused a repeat length-dependent increase in aggregate formation, implying that the proteasome plays a direct role in suppressing polyglutami ne aggregation in disease. These results support a central role for protein misfolding in the pathogenesis of SCA3/MJD and suggest that modulating pro teasome activity is a potential approach to altering the progression of thi s and other polyglutamine diseases.