Huntington's Disease (HD) is an Inherited brain disorder affecting approximately 1 in 10,000 Canadians that causes progressive disability with an inexorable march towards death averaging 18 years after the onset of symptoms. There is currently no cure for HD and no known treatment that affects the age of onset or the progression of symptoms. The underlying genetic defect that causes HD is now known and the mutant HD gene produces an abnormal protein called huntingtin (htt) that damages brain cells. Many research groups around the world are studying how the abnormal htt protein kills cells, but the normal cellular function of htt is not well understood. This proposal is unique in that we will examine the protective role that the normal htt protein may play in the disease process of HD. We previously demonstrated that the normal htt protein has a pro-survival function in the brain and prevents various forms of brain cell death. Our proposed experiments will determine what specific regions of htt are required for this protective role, how protein modifications of htt affect this function, and we will test what effect modulating levels of normal htt have on the progression and development of HD. Based on our preliminary results, I hypothesize that altering the pro-survival function of htt will modulate the process of brain cell injury in HD. Mapping the critical pro-survival regions of htt, investigating the mechanisms by which this function is regulated, and understanding the downstream pathways by which htt modulates brain cell death may provide novel cellular therapeutic targets for HD and for neurodegenerative disorders in general.