Spinocerebellar ataxia type 1 (SCA1) is an untreatable fatal autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ATXN1. Previous work has shown that the sub cellular deposition and localization of mutant ATXN1 plays a critical role in the pathogenesis of SCA1. For many proteins, the peptide backbone is often altered by post-translational modifications (PTMs) and covalent attachment of chemical groups that change the properties, and hence the function of proteins. ATXN1 is modified by phosphorylation at two sites, S776 and S239. In addition this protein is sumoylated at a minimum of five lysine residues, one of which is in the AXH domain a region of ATXN1 important for several crucial interactions. Thus the goal of the studies proposed in this application is to elucidate the pathways that lead to the phosphorylation and sumoylation of ATXN1 in vivo. We will assess the extent to which the post-translational modification of ATXN1 impact its biology, in particular the ability of mutant ATXN1 to cause the degeneration of cerebella Purkinje cells.

Public Health Relevance

In undertaking these studies we are focused on testing two hypotheses: 1) Post- translation modifications are important for regulating the normal function of ATXN1 and pathogenesis induced by mutant ATXN1, and 2) As such they are targets for development of treatments for SCA1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045667-10
Application #
8245795
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Gwinn, Katrina
Project Start
2003-08-15
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$393,348
Indirect Cost
$130,004
Name
University of Minnesota Twin Cities
Department
Pathology
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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