Research Grant Award

Sue M Travis, PhD

University of Iowa
Effects of Polyglutamine Expansion on Activity of Ataxin-3, the Spinocerebellar Ataxia 3 Disease Protein

Spinocerebellar Ataxia 3, also known as Machado-Joseph Disease (SCA 3/MJD), may be the most common dominantly inherited ataxia. It is one of several neurodegenerative disorders that are caused by the expression of mutant proteins containing an expanded polyglutamine region. The SCA 3 gene encodes the protein ataxin-3, but little is known about ataxin-3 function in cells, and how it is affected by expansion of the polyglutamine region. Ataxin-3 has been shown to be a deubiquitinating enzyme that may have a role in the ubiquitin proteasome protein degradation pathway. It binds polyubiquitin chains through its ubiquitin interacting domain and it cleaves these chains through its protease catalytic domain. In addition, ataxin-3 interacts with other cellular ubiquitin binding proteins, and these interactions may regulate or mediate ataxin-3 activity.

The physiological functions of attain-3 and its interactions with ubiquitin chains and other proteins are not well understood. Most importantly, it is not clear how an expanded polyQ region alters the activity of ataxin-3, and how this alteration leads to neurodegeneration. We recently identified specific ubiquitin chains that are the preferred target of ataxin-3, and we must investigate the effects of polyglutamine expansion on binding and cleavage of these chains.

In the proposed work, we will test the hypothesis that expanded polyglutamine region alters AT3 Ub chain cleavage and binding properties, as well as its interactions with other cellular proteins. We anticipate that our results will answer important basic biological questions about AT3 function in cells, and we may be applicable to other plygultamine diseases as well.