Interference by Huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity

Expanded polyglutamine repeats have been proposed to cause neuronal degener ation in Huntington's disease (HD) and related disorders, through abnormal interactions with other proteins containing short polyglutamine tracts such as the transcriptional coactivator CREB binding protein, CBP. We found tha t CBP was depleted from its normal nuclear Location and was present in poly glutamine aggregates in HD cell culture models, HD transgenic: mice, and hu man HD postmortem brain. Expanded polyglutamine repeats specifically interf ere with CBP-activated gene transcription, and overexpression of CBP rescue d polyglutamine-induced neuronal toxicity. Thus, polyglutamine-mediated int erference with CBP-regulated gene transcription may constitute a genetic ga in of function, underlying the pathogenesis of polyglutamine disorders.