Abstract
Spinocerebellar ataxia type 3 (SCA3) belongs to the family of polyglutamine neurodegenerations. Each disorder stems from the abnormal lengthening of a glutamine repeat in a different protein. Although caused by a similar mutation, polyglutamine disorders are distinct, implicating non-polyglutamine regions of disease proteins as regulators of pathogenesis. SCA3 is caused by polyglutamine expansion in ataxin-3. To determine the role of ataxin-3's non-polyglutamine domains in disease, we utilized a new, allelic series of Drosophila melanogaster. We found that ataxin-3 pathogenicity is saliently controlled by polyglutamine-adjacent ubiquitin-interacting motifs (UIMs) that enhance aggregation and toxicity. UIMs function by interacting with the heat shock protein, Hsc70-4, whose reduction diminishes ataxin-3 toxicity in a UIM-dependent manner. Hsc70-4 also enhances pathogenicity of other polyglutamine proteins. Our studies provide a unique insight into the impact of ataxin-3 domains in SCA3, identify Hsc70-4 as a SCA3 enhancer, and indicate pleiotropic effects from HSP70 chaperones, which are generally thought to suppress polyglutamine degeneration.
Highlights
Spinocerebellar ataxia type 3 (SCA3; known as Machado-Joseph disease) is the most frequent dominant ataxia worldwide
We selected this approach as SCA3 is adult-onset and progressive and because neurons are the type of cell impacted
We found that the ubiquitininteracting motifs (UIMs) of ataxin-3 are key players in pathogenicity through an unexpected role from Hsc70-4, which exacerbates SCA3
Summary
Spinocerebellar ataxia type 3 (SCA3; known as Machado-Joseph disease) is the most frequent dominant ataxia worldwide. SCA3 is caused by CAG repeat expansion in the gene ATXN3 that is normally 12–42 repeats long but is expanded to ~60–87 repeats in patients (Todi et al, 2007b; Costa and Paulson, 2012). This triplet repeat encodes a polyglutamine (polyQ) tract in the protein, ataxin-3, a deubiquitinase (DUB; Figure 1) implicated in protein quality control and DNA repair (Costa and Paulson, 2012; Dantuma and Herzog, 2020). While studies of other polyQ diseases provided insight into the role of protein context in polyQ
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