Journal
NEUROBIOLOGY OF DISEASE
Volume 116, Issue -, Pages 78-92Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2018.04.013
Keywords
AAA ATPase; Ataxia; Ataxin-3; Deubiquitinase; Machado-Joseph Disease; Neurodegeneration; Polyglutamine; Spinocerebellar Ataxia Type 3; VCP/p97
Categories
Funding
- Wayne State University Thomas Rumble Fellowship
- NINDS [F31NS095575, R01NS086778]
- Department of Pharmacology at Wayne State University
- [R01NS038712]
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Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat. We examined the importance of this interaction in ataxin-3dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP-binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA -interference has a similar, protective effect to mutating the VCP-binding site of pathogenic ataxin-3. Based on in vivo pulse-chases, aggregated species of ataxin-3 are highly stable, in a manner independent of VCP-binding. Collectively, our results highlight an important role for the ataxin-3-VCP interaction in SCA3, based on a model that posits a seeding effect from VCP on pathogenic ataxin-3 aggregation and subsequent toxicity.
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