Eight neurodegenerative diseases are caused by expansion of glutamine tracts in proteins, including spinal cerebellar ataxias, DRPLA, Huntington's disease and Kennedy's disease. It is unclear why expanded polyglutamine tracts are toxic and there is no treatment for these diseases. We have developed a C. elegans overexpression model for polyglutamine neurotoxicity by expressing huntingtin protein fragments in neurons and we will assess the toxic activity of mutant ataxin-1 and ataxin-3 in these same C. elegans neurons. Mutation of pqe-1 specifically and strongly enhances polyQ toxicity in C. elegans. We will clone and characterize pqe-1. We will characterize and clone additional enhancer genes and will identify, characterize and clone suppressor genes. The corresponding proteins are candidate modifiers of polyglutamines toxicity in Huntington's and other polyglutamine diseases. We will generate mutations in C. elegans homologs of huntintin, ataxin-1 and ataxin-3 to address their role in the nervous system and in neurodegeneration. The relationship between these genes, polyglutamine toxicity, the apoptotic pathway and other candidate genes will be assessed. We will identify human homologs of enhancer and suppressor genes identified in our genetic screens and assess their role in polyglutamine toxicity in other model organisms to address the relevance of these candidate genes to human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040048-03
Application #
6625487
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
2000-12-15
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
3
Fiscal Year
2003
Total Cost
$346,000
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Dimitriadi, Maria; Hart, Anne C (2010) Neurodegenerative disorders: insights from the nematode Caenorhabditis elegans. Neurobiol Dis 40:4-11
Voisine, Cindy; Varma, Hemant; Walker, Nicola et al. (2007) Identification of potential therapeutic drugs for huntington's disease using Caenorhabditis elegans. PLoS One 2:e504
Jia, Kailiang; Hart, Anne C; Levine, Beth (2007) Autophagy genes protect against disease caused by polyglutamine expansion proteins in Caenorhabditis elegans. Autophagy 3:21-5