Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder caused by the expansion of a glutamine repeat within the SCA1-encoded protein ataxin-1. Previous work has shown that the subcellular deposition and localization of mutant ataxin-1 plays a critical role in the pathogenesis of SCA1. A key player in numerous cell-signaling pathways, many associated with neurodegeneration, is the enzyme glycogen synthase kinase 3 (GSK3). Our results indicate that serines 776 and 780 of ataxin-1 play a role in the subcellular localization of this protein, perhaps via their phosphorylation by GSK3b. Thus, the goal of the research described below is to determine whether cell-signaling pathways acting through these serines of ataxin-1 are biologically relevant GSK3b has recently emerged as a key target in drug discovery. If it proves to be the case that SCA1 pathogenesis is associated with increased levels of GSK3b activity, GSK3b inhibitors might have a therapeutic role in SCA1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045667-02
Application #
6787671
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Gwinn, Katrina
Project Start
2003-08-15
Project End
2008-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$411,171
Indirect Cost
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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Keiser, Megan S; Kordower, Jeffrey H; Gonzalez-Alegre, Pedro et al. (2015) Broad distribution of ataxin 1 silencing in rhesus cerebella for spinocerebellar ataxia type 1 therapy. Brain 138:3555-66
Cvetanovic, M; Ingram, M; Orr, H et al. (2015) Early activation of microglia and astrocytes in mouse models of spinocerebellar ataxia type 1. Neuroscience 289:289-99
Dahlin, Jayme L; Walters, Michael A (2014) The essential roles of chemistry in high-throughput screening triage. Future Med Chem 6:1265-90
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Ebner, Blake A; Ingram, Melissa A; Barnes, Justin A et al. (2013) Purkinje cell ataxin-1 modulates climbing fiber synaptic input in developing and adult mouse cerebellum. J Neurosci 33:5806-20
Orr, Harry T (2012) Cell biology of spinocerebellar ataxia. J Cell Biol 197:167-77

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