The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription

Huntington's Disease (HD) is caused by an expansion of a polyglutamine trac t within the huntingtin (htt) protein. Pathogenesis in HD appears to includ e the cytoplasmic cleavage of htt and release of an amino-terminal fragment capable of nuclear localization. We have investigated potential consequenc es to nuclear function of a pathogenic amino-terminal region of htt (httex1 p) including aggregation, protein-protein interactions, and transcription. httex1p was found to coaggregate with p53 in inclusions generated in cell c ulture and to interact with p53 in vitro and in cell culture. Expanded htte x1p represses transcription of the p53-regulated promoters, p21(WAF1/CIP1) and MDR-1, httex1p was also found to interact in vitro with CREB-binding pr otein (CBP) and mSin3a. and CBP to localize to neuronal intranuclear inclus ions in a transgenic mouse model of Ho. These results raise the possibility that expanded repeat htt causes aberrant transcriptional regulation throug h its interaction with cellular transcription factors which may result in n euronal dysfunction and cell death in HD.