Huntington Disease (HD) is an incurable neurodegenerative disease. There are no effective therapies. Further, in general, little is known about molecular mechanisms that might be targeted to block the misfolding and aggregation of the mutant huntingtin protein, which is the cause of the disorder. The Diamond laboratory previously identified a lead compound that blocks pathology in cells and animal models of HD. This grant will directly test the presumed mechanism of this compound, which involves the interaction of a ubiquitous cellular protein (profilin) with the huntingtin protein. The experiments proposed will determine exactly how profilin interacts with huntingtin to block huntingtin’s pathological aggregation, and what are the consequences of this interaction for the structure of huntingtin. This work will elucidate the precise molecular mechanism of the lead compound, and could lead to a better understanding of how to treat HD.