The long-term objective of the research described herein is to determine the molecular basis of a cluster of neurological disorders known as the polyglutamine diseases. They are all hereditary, adult-onset conditions characterized by progressive deterioration the nervous system. These diseases share a common genetic basis, common pathological features, and common mechanisms at the molecular level. The genetic mutation in these diseases leads to the production of a protein with an abnormally long tract of the amino acid glutamine that endows the mutant proteins with a gain-of-function that is toxic to neurons. A growing body of evidence suggests that transcriptional dysregulation may be a primary pathogenic process in polyglutamine disease. Our own preliminary studies suggest that components of the histone acetyltransferase machinery may be primary targets for expanded polyglutamine. Thus, we hypothesize that polyglutamine-induced neurodegeneration is a consequence of altered transcription resulting from defective histone acetylation. We hypothesize further that altered transcription ultimately leads to inappropriate mobilization of cell death machinery that contributes to neurodegeneration. To test these hypotheses, the following, specific aims will be addressed:
Specific Aim 1) To test our working hypothesis that the toxicity of expanded polyglutamine is a consequence of defective histone acetylation using a Drosophila model system.
Specific Aim 2) To identify the cadre of genes involved in mediating neurodegeneration in a Drosophila model of polyglutamine disease.
Specific Aim 3) To identify the biochemical pathways that mediate polyglutamine-induced apoptosis in neuronal cell culture.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Career Transition Award (K22)
Project #
5K22NS044125-04
Application #
7162979
Study Section
NST-2 Subcommittee (NST)
Program Officer
Sutherland, Margaret L
Project Start
2004-01-15
Project End
2007-06-30
Budget Start
2007-01-01
Budget End
2007-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$81,000
Indirect Cost
Name
University of Pennsylvania
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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