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Article

  • The EMBO Journal (2008) 27, 827 - 839
  • doi:10.1038/emboj.2008.23

Published online: 21 February 2008

Mutant Huntingtin reduces HSP70 expression through the sequestration of NF-Y transcription factor

Tomoyuki Yamanaka1,2, Haruko Miyazaki1, Fumitaka Oyama1, Masaru Kurosawa1, Chika Washizu1, Hiroshi Doi1 and Nobuyuki Nukina1

  1. Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama, Japan
  2. Special Postdoctoral Researchers Program, RIKEN, Saitama, Japan

Correspondence to:

Nobuyuki Nukina, Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. Tel.: +81 48 467 9702; Fax: +81 48 462 4796; E-mail: nukina@brain.riken.jp

Received 25 September 2007; Accepted 30 January 2008

In Huntington's disease (HD), mutant Huntingtin, which contains expanded polyglutamine stretches, forms nuclear aggregates in neurons. The interactions of several transcriptional factors with mutant Huntingtin, as well as altered expression of many genes in HD models, imply the involvement of transcriptional dysregulation in the HD pathological process. The precise mechanism remains obscure, however. Here, we show that mutant Huntingtin aggregates interact with the components of the NF-Y transcriptional factor in vitro and in HD model mouse brain. An electrophoretic mobility shift assay using HD model mouse brain lysates showed reduction in NF-Y binding to the promoter region of HSP70, one of the NF-Y targets. RT–PCR analysis revealed reduced HSP70 expression in these brains. We further clarified the importance of NF-Y for HSP70 transcription in cultured neurons. These data indicate that mutant Huntingtin sequesters NF-Y, leading to the reduction of HSP70 gene expression in HD model mice brain. Because suppressive roles of HSP70 on the HD pathological process have been shown in several HD models, NF-Y could be an important target of mutant Huntingtin.

  • Keywords:

    • heat shock protein,
    • Huntington's disease,
    • NF-Y,
    • transcription