Nine inherited neurodegenerative disorders are caused by an expansion of a polyglutamine tract in the associated disease proteins. Increasing evidence indicates that huntingtin containing an expanded polyglutamine tract accumulates in the nucleus and affects gene expression in Huntington disease (HD). Transcriptional dysregulation may also be the major pathological cause in SCA17 in which polyglutamine expansion is present in the TATA binding protein (TBP). HD and SCA17 show similar neurological phenotypes and neuropathology characterized by neurodegeneration in the striatum and cortex, suggesting that both diseases may share a similar pathological mechanism. Although recent studies have shown that mutant huntingtin binds to the transcriptional factors Sp1 and TAF130, the mechanism by which mutant polyglutamine proteins affect gene expression remains to be investigated. Furthermore, it is unclear how the abnormal interactions between mutant polyglutamine proteins and transcription factors contribute to the disease process. We hypothesize that soluble polyglutamine proteins interfere with gene expression by altering the interactions between transcription factors and their DNA targets before the formation of large nuclear inclusions. To test this hypothesis, we will (1) study how mutant N-terminal huntingtin abnormally binds to Sp1 to affect gene expression, (2) investigate whether polyglutamine expansion causes TBP to abnormally bind to the TATA box and its associated factors, and (3) examine whether polyglutamine expansion causes TBP and huntingtin to abnormally bind to the transcriptional factor TAF130, leading to a common transcriptional defect that may contribute to the similar neuropathology in HD and SCA17. These studies aim to provide insights into the mechanism by which polyglutamine expansion affects gene expression. They will also help identify a therapeutic target for the treatment of polyglutamine diseases ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045016-05
Application #
7384999
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Sutherland, Margaret L
Project Start
2004-03-01
Project End
2009-02-28
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
5
Fiscal Year
2008
Total Cost
$234,835
Indirect Cost
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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