TY - JOUR TI - Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation AU - Johnson, Sean L AU - Ranxhi, Bedri AU - Libohova, Kozeta AU - Tsou, Wei-Ling AU - Todi, Sokol V A2 - VijayRaghavan, K A2 - Albin, Roger A2 - Pandey, Udai VL - 9 PY - 2020 DA - 2020/09/21 SP - e60742 C1 - eLife 2020;9:e60742 DO - 10.7554/eLife.60742 UR - https://doi.org/10.7554/eLife.60742 AB - 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. KW - ataxia KW - aggregation KW - neurodegeneration KW - deubiquitinase KW - proteostasis KW - machado-joseph disease JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -