Abstract: In general, the invention provides methods, reagents, and uses for modulating cell survival. In various alternative aspects, the invention provides methods of modulating cell survival by administering a huntingtin protein or a biologically-active fragment or variant thereof, or methods of treatment or prophylaxis of a cell degenerative disease or a cell proliferative disease by administering a huntingtin protein or a biologically-active fragment or variant thereof. In various alternative aspects, the invention provides diagnostic assays or methods of assaying test compounds using a huntingtin protein or a biologically-active fragment or variant thereof.

Abstract: A family of proteins, including a specific human protein designated as HIP1, has been identified that interact differently with the gene product of a normal (16 CAG repeat) and an expanded (>44 CAG repeat) HD gene. Expression of the HIP1 protein was found to be enriched in the brain. Analysis of the sequence of the HIP1 protein indicated that it includes a death effector domain (DED), suggesting an apoptotic function. Thus, it appears that a normal function of Huntingtin may be to bind HIP1 and related apoptosis modulators, reducing its effectiveness in stimulating cell death. Since expanded huntingtin performs this function less well, there is an increase in HIP1-modulated cell death in individuals with an expanded repeat in the HD gene. This understanding of the likely role of huntingtin and HIP1 or related proteins (collectively “HIP-apoptosis modulating proteins”) in the pathology of Huntington's Disease offers several possibilities for therapy.