DESCRIPTION (summarized from the abstract): This proposal addresses biochemical and cellular mechanisms of pathogenesis in Huntington's Disease. To do this, 3 specific aims are proposed. In the first aim, a characterization of the N-terminus of the huntingtin protein is proposed, and a characterization of proteins that interact with huntingtin. This will define the degree to which the Huntingtin protein is truncated in the cell, and what proteins might interact with the pathological protein. In the second aim, a characterization will be performed of huntingtin and its interacting proteins in cell model experiments using transient transfection techniques. Cleavage sites and interaction domains defined in specific aim 1 will be tested for the effects on protein localization and function. In specific aim 3, the effect of truncation of the huntingtin protein and interaction with other proteins in the cell on toxicity will be addressed. This will be addressed using both cell lines and primary neuronal cultures.