Ubiquitin-interacting motifs of ataxin-3 regulate its polyglutamine toxicity through Hsc70-4-dependent aggregation.

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.

• Authors: Sean L Johnson, Bedri Ranxhi, Kozeta Libohova, Wei-Ling Tsou, Sokol V Todi
• Journal: eLife (Elife) Vol. 9 (09 21 2020) ISSN: 2050-084X [Electronic] England
• PMID: 32955441 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020, Johnson et al.

Chemical References

• Drosophila Proteins
• HSC70 Heat-Shock Proteins
• Hsc70-4 protein, Drosophila
• Peptides
• Ubiquitin
• polyglutamine
• Ataxin-3

Topics

• Amino Acid Motifs
• Animals
• Ataxin-3 (chemistry, genetics, metabolism, toxicity)
• Drosophila
• Drosophila Proteins (chemistry, metabolism)
• HSC70 Heat-Shock Proteins (chemistry, metabolism)
• Humans
• Larva (metabolism)
• Machado-Joseph Disease (genetics)
• Peptides (chemistry, genetics, metabolism, toxicity)
• Ubiquitin (chemistry, metabolism)