Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss o f function of transcriptional coactivator proteins have been implicated in the pathogenesis of these diseases(1). Huntington's disease is caused by ex pansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing do main of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransfe rase domains of two distinct proteins: CREB-binding protein (CBP) and p300/ CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits t he acetyltransferase activity of at least three enzymes: p300, P/CAF and CB P. Expression of Httex1p in cultured cells reduces the level of the acetyla ted histones H3 and H4, and this reduction can be reversed by administering inhibitors of histone deacetylase (HDAC). In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat e xpansion, and they reduce lethality in two Drosophila models of polyglutami ne disease. These findings raise the possibility that therapy with HDAC inh ibitors may slow or prevent the progressive neurodegeneration seen in Hunti ngton's disease and other polyglutamine-repeat diseases, even after the ons et of symptoms.