The most common dominantly inherited ataxia, Spinocerebellar Ataxia Type 3 (SCA3) is also one of nine neurodegenerative diseases caused by polyglutamine expansion. Although polyglutamine diseases share common features centered on protein misfolding, it is increasingly clear that the pathogenesis of SCA3 and other polyglutamine diseases depends greatly on the specific protein context in which the expansion occurs. The studies proposed here extend our longstanding efforts to understand both the disease mechanisms underlying SCA3 and the normal and disease-related functions of the SCA3 disease protein, a de-ubiquitinating enzyme called ataxin-3. The four proposed aims will investigate key unanswered questions in SCA3 and establish important new model systems.
Aim 1 will test whether ataxin-3 normally suppresses polyglutamine neurodegeneration by virtue of its activity as a ubiquitin chain editing enzyme and whether polyglutamine expansion in ataxin-3 alters this activity.
Aim 2 will address structure-function relationships for this apparently unique enzyme, building on our recent discovery that mono-ubiquitination of ataxin-3 directly enhances its enzymatic activity.
Aim 3 will define the basis of early electrophysiologic changes in the cerebellum of SCA3 transgenic mice and test whether these changes can be modified by channel modulators. Finally, Aim 4 will complete our development of SCA3 knock-in mice, bringing to the research field a genetically precise mouse model of SCA3 that is clearly needed. Together these studies are expected to provide new understanding of the biochemical and cellular processes by which SCA3 occurs and identify potential routes to therapy for this fatal neurodegenerative disease.

Public Health Relevance

Spinocerebellar ataxia type 3 is the most common dominantly inherited ataxia and one of nine diseases caused by polyglutamine expansion. This grant will explore the basis of SCA3 in order that we can ultimately develop therapies for this fatal disease based on a better understanding of disease mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038712-14
Application #
8213738
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gwinn, Katrina
Project Start
2000-01-01
Project End
2015-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$512,357
Indirect Cost
$138,940
Name
University of Michigan Ann Arbor
Department
Neurology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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