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

Tomoyuki Yamanaka, Haruko Miyazaki, Fumitaka Oyama, Masaru Kurosawa, Chika Washizu, Hiroshi Doi, Nobuyuki Nukina

Research output: Contribution to journalArticlepeer-review

87 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)827-839
Number of pages13
JournalEMBO Journal
Volume27
Issue number6
DOIs
Publication statusPublished - Mar 19 2008
Externally publishedYes

Keywords

  • Heat shock protein
  • Huntington's disease
  • NF-Y
  • Transcription

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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