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Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2001. "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila," Nature, Nature, vol. 413(6857), pages 739-743, October.
  • Handle: RePEc:nat:nature:v:413:y:2001:i:6857:d:10.1038_35099568
    DOI: 10.1038/35099568
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    Cited by:

    1. Pawel Lisowski & Selene Lickfett & Agnieszka Rybak-Wolf & Carmen Menacho & Stephanie Le & Tancredi Massimo Pentimalli & Sofia Notopoulou & Werner Dykstra & Daniel Oehler & Sandra López-Calcerrada & Ba, 2024. "Mutant huntingtin impairs neurodevelopment in human brain organoids through CHCHD2-mediated neurometabolic failure," Nature Communications, Nature, vol. 15(1), pages 1-27, December.
    2. Antonella Cardinale & Emanuela Paldino & Carmela Giampà & Giorgio Bernardi & Francesca R Fusco, 2015. "PARP-1 Inhibition Is Neuroprotective in the R6/2 Mouse Model of Huntington’s Disease," PLOS ONE, Public Library of Science, vol. 10(8), pages 1-22, August.
    3. Shuang Qiu & Chengfeng Xiao & R Meldrum Robertson, 2016. "Pulsed Light Stimulation Increases Boundary Preference and Periodicity of Episodic Motor Activity in Drosophila melanogaster," PLOS ONE, Public Library of Science, vol. 11(9), pages 1-16, September.

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