1. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
- Author
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David E. Housman, Marilee Greenwald, Marnix Poelman, Emily Schmidt, Joan S. Steffan, Alexsey Kazantsev, George R. Jackson, László Bodai, J. Lawrence Marsh, Judit Pallos, Alexander McCampbell, Leslie M. Thompson, Barbara L. Apostol, Ya-Zhen Zhu, and Riki Kurokawa
- Subjects
Repetitive Sequences, Amino Acid ,Huntingtin ,Saccharomyces cerevisiae Proteins ,Glutamine ,Nerve Tissue Proteins ,PC12 Cells ,Histone Deacetylases ,Animals, Genetically Modified ,Histones ,Acetyltransferases ,Huntingtin Protein ,medicine ,Animals ,Drosophila Proteins ,CREB-binding protein ,Enzyme Inhibitors ,Glutathione Transferase ,Histone Acetyltransferases ,Histone deacetylase 5 ,Multidisciplinary ,biology ,Neurodegeneration ,Nuclear Proteins ,Acetylation ,Neurodegenerative Diseases ,medicine.disease ,CREB-Binding Protein ,Cell biology ,Protein Structure, Tertiary ,Rats ,Histone Deacetylase Inhibitors ,Repressor Proteins ,Disease Models, Animal ,Sin3 Histone Deacetylase and Corepressor Complex ,Huntington Disease ,Biochemistry ,Gene Expression Regulation ,Acetyltransferase ,Nerve Degeneration ,biology.protein ,Trans-Activators ,Drosophila ,Histone deacetylase ,Trinucleotide repeat expansion ,Peptides ,E1A-Associated p300 Protein - Abstract
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.
- Published
- 2001