Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, California 92697, USA.
Department of Developmental and Cell Biology, University of California, Irvine, California 92697, USA.
Neurogenetics Branch, NINDS, NIH, 10/3B14, 10 Center Drive, MSC 1250, Bethesda, Maryland 20892, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA.
Department of Neurology, University of California, Los Angeles, California 90095, USA.
Proteins with expanded polyglutamine repeats cause Huntington's disease and other neurodegenerative diseases. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Huntington's disease is caused by expansion of a repeated sequence of the amino acid glutamine in the abnormal protein huntingtin (Htt). Here we show that the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF). In cell-free assays, Httex1p also inhibits the acetyltransferase activity of at least three enzymes: p300, P/CAF and CBP. Expression of Httex1p in cultured cells reduces the level of the acetylated 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 expansion, and they reduce lethality in two Drosophila models of polyglutamine disease. These findings raise the possibility that therapy with HDAC inhibitors may slow or prevent the progressive neurodegeneration seen in Huntington's disease and other polyglutamine-repeat diseases, even after the onset of symptoms.