Huntington's disease is a progressive neurodegenerative disorder caused by expansion of a polyglutamine (polyQ) repeat in the huntingtin protein. We previously reported a role of p53 in the mitochondria-associated cellular dysfunction and behavioral abnormalities of Huntington’s disease (HD) (Bae et al, SFN abstract 2003). Here we present new evidences further supporting a crucial role of p53 in HD. First, we confirmed in vitro protein binding of Huntingtin (Htt) to p53 in a polyQ-dependent manner. Consistently, both endogenous N-terminal fragment and full length Htt co-precipitate with p53. Transcriptional activity of p53 is augmented by mutant Htt (mHtt) in the nucleus, resulting in upregulation of several p53 target proteins that are functionally associated with mitochondria, including Bax and Puma. In addition to the normalization of behavioral abnormalities in mHtt transgenic (mHtt-Tg) mice by genetic deletion of p53, mHtt-Tg flies in a p53 null background are resistant to mHtt-induced neurodegenerati...