Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

By J. Steffan, L. Bodai, J. Pallos, M. Poelman, Alexander McCampbell, Barbara L. Apostol, A. Kazantsev, E. Schmidt, Ya-zhen Zhu, Marilee Greenwald and 4 more. Nature, 2001

1,237 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fed2a5383fe23c503b2d4d90ee27c9f1724ad952

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Citations in the corpus

Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice (2003, neutral): “…binding of the mutant huntingtin protein or cleaved products to a number of transcription factors, disrupting the normal pattern of gene transcription and resulting in functional and degenerative changes (Cha, 2000; McCampbell et al., 2000; Steffan et al., 2000, 2001; Sugars and Rubinsztein, 2003).”
Disruption of axonal transport by loss of huntingtin or expression of pathogenic polyQ proteins in Drosophila. (2003, neutral): “For example, induced cytoplasmic accumulations and these accumuin mouse models, both loss (Dragatsis et al., 2000) and lations may promote abnormal protein-protein intergain of function of htt causes neurodegeneration (Man- actions that could trigger a cascade of toxic events, giarini et al., 1996; ”
Multiple roles of HDAC inhibition in neurodegenerative conditions (2009, background): “It is well known that the genetic mutation responsible for HD is an expansion of a CAG trinucleotide repeat encoding polyglutamine (polyQ) in the first exon of the huntingtin (HTT) gene.”