Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

Joan S. Steffan, Laszlo Bodai, Judit Pallos, Marnix Poelman, Alexander McCampbell, Barbara L. Apostol, Alexsey Kazantsev, Emily Schmidt, Ya-Zhen Zhu, Marilee Greenwald, Riki Kurokawa, David E. Housman, George R. Jackson, J. Lawrence Marsh and Leslie M. Thompson ()
Additional contact information
Joan S. Steffan: Gillespie 2121, University of California
Laszlo Bodai: University of California
Judit Pallos: University of California
Marnix Poelman: Gillespie 2121, University of California
Alexander McCampbell: Neurogenetics Branch, NINDS, NIH, 10/3B14
Barbara L. Apostol: Gillespie 2121, University of California
Alexsey Kazantsev: Massachusetts Institute of Technology
Emily Schmidt: Gillespie 2121, University of California
Ya-Zhen Zhu: Gillespie 2121, University of California
Marilee Greenwald: Gillespie 2121, University of California
Riki Kurokawa: University of California, San Diego
David E. Housman: Massachusetts Institute of Technology
George R. Jackson: University of California
J. Lawrence Marsh: University of California
Leslie M. Thompson: Gillespie 2121, University of California

Nature, 2001, vol. 413, issue 6857, 739-743

Abstract: 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 diseases1. 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.

Date: 2001
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DOI: 10.1038/35099568

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