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Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

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.

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Figure 1: Htt interacts with the acetyltransferase (AT) domain of CBP and P/CAF in vitro.
Figure 2: Htt inhibits the acetyltransferase activity of CBP, p300 and P/CAF in vitro.
Figure 3: A reduction in acetylation of histones H3 and H4 is induced by Htt expression in cell culture.
Figure 4: In vivo consequences of altered acetyltransferase function.

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Acknowledgements

We thank K. Fischbeck for discussions and information regarding SAHA, E. Wanker for the GST–Htt fusion protein constructs, and E. Schweitzer for the gift of PC12 cell pellets. This work was supported by the Hereditary Disease Foundation's Cure HD Initiative, the Huntington's Disease Society of America, Human Frontier Science Program and grants from the National Institutes of Health. This work was made possible in part by access to the Optical Biology Shared Resource of the Cancer Center Support Grant at the University of California, Irvine, and the National Drosophila Stock Center.

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Correspondence to Leslie M. Thompson.

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Steffan, J., Bodai, L., Pallos, J. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001). https://doi.org/10.1038/35099568

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