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Access Type

WSU Access

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Sokol V. Todi

Abstract

The polyglutamine (polyQ) disease family is composed of nine neurodegenerative diseases caused by CAG trinucleotide repeat expansions in the associated genes. Although these diseases are caused by similar mutations, the polyQ proteins are otherwise structurally and functionally unique. Thus, the protein domains surrounding the polyQ tracts, as well as their interacting partners, are thought to be critical to the pathogenesis of these clinically distinct diseases. Spinocerebellar ataxia type 3 is caused by polyQ expansion of ataxin-3, a deubiquitinating enzyme implicated in protein quality control, transcriptional regulation, and DNA repair. Rad23 and VCP are two of ataxin-3’s protein quality control partners that bind at its Ubiquitin-binding site 2 and VCP-binding site, respectively. To learn more about protein context in SCA3, we generated new transgenic Drosophila lines that express pathogenic ataxin-3 with these protein-binding sites intact or mutated. Through a battery of physiological and biochemical assays, we observed that ataxin-3’s interaction with Rad23 regulates the stability, autoprotection, and toxicity of the SCA3 protein. We also find that VCP can modulate the aggregation propensity and subsequent toxicity of ataxin-3. Altogether, our findings provide insight into SCA3 biology and potential avenues for therapeutic intervention.

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