Mechanisms Responsible for and Involvement of Elevated Levels of p53 in HD

Increasing evidence suggests that the pro-apoptotic protein p53 may playa role in mediating neurodegeneration in a wide array of neurodegenerative conditions. Based on previous studies, and preliminary data within this proposal, we hypothesize that alterations inp53 playa direct role in mediating neurotoxicity and neural death observed in HD. Additionally, because of the availability of a large number of pharmacological p53 inhibitors, we propose that modulation of p53 may serve as a target for effective therapeutic interventions in HD. The studies outlined in this proposal will employ in vitro and in vivo models of HD to test our hypothesis, utilizing the following specific aims: (1) To identify changes in p53 expression and p53 activity in in vitro and in vivo models of HD (2) To determine the role of p53 in HD-associated alterations in mitochondrial function, caspase activation, and neural death in an in vitro model of HD (3) To determine the neuroprotective effects of pharmacological inhibition ofp53 in an in vivo model of HD. Taken together, these data will provide the basis for understanding the contribution of p53 to HD, and identify the therapeutic potential of p53 inhibitors in the treatment of HD.