Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction

Tomoyuki Yamanaka, Asako Tosaki, Haruko Miyazaki, Masaru Kurosawa, Yoshiaki Furukawa, Mizuki Yamada, Nobuyuki Nukina

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

In polyglutamine diseases including Huntington's disease (HD), mutant proteins containing expanded polyglutamine stretches form nuclear aggregates in neurons. Although analysis of their disease models suggested a significance of transcriptional dysregulation in these diseases, how it mediates the specific neuronal cell dysfunction remains obscure. Here we performed a comprehensive analysis of altered DNA binding of multiple transcription factors using R6/2 HD model mice brains that express an N-terminal fragment of mutant huntingtin (mutant Nhtt). We found a reduction of DNA binding of Brn-2, a POU domain transcription factor involved in differentiation and function of hypothalamic neurosecretory neurons. We provide evidence supporting that Brn-2 loses its function through two pathways, its sequestration by mutant Nhtt and its reduced transcription, leading to reduced expression of hypothalamic neuropeptides. In contrast to Brn-2, its functionally related protein, Brn-1, was not sequestered by mutant Nhtt but was upregulated in R6/2 brain, except in hypothalamus. Our data indicate that functional suppression of Brn-2 together with a regionspecific lack of compensation by Brn-1 mediates hypothalamic cell dysfunction by mutant Nhtt.

Original languageEnglish
Article numberddq087
Pages (from-to)2099-2112
Number of pages14
JournalHuman Molecular Genetics
Volume19
Issue number11
DOIs
Publication statusPublished - 2010 Feb 25
Externally publishedYes

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POU Domain Factors
Neurons
DNA
Huntington Disease
Brain
Mutant Proteins
Neuropeptides
Hypothalamus
Transcription Factors
Proteins
polyglutamine

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology
  • Medicine(all)

Cite this

Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction. / Yamanaka, Tomoyuki; Tosaki, Asako; Miyazaki, Haruko; Kurosawa, Masaru; Furukawa, Yoshiaki; Yamada, Mizuki; Nukina, Nobuyuki.

In: Human Molecular Genetics, Vol. 19, No. 11, ddq087, 25.02.2010, p. 2099-2112.

Research output: Contribution to journalArticle

Yamanaka, Tomoyuki ; Tosaki, Asako ; Miyazaki, Haruko ; Kurosawa, Masaru ; Furukawa, Yoshiaki ; Yamada, Mizuki ; Nukina, Nobuyuki. / Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 11. pp. 2099-2112.
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