C. ELEGANS MODEL FOR POLYGLUTAMINE TOXICITY

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DESCRIPTION (From the Applicant's Abstract): 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.