ATF3 plays a protective role against toxicity by N-terminal fragment of mutant huntingtin in stable PC12 cell line

Yideng Liang, Haibing Jiang, Tamara Ratovitski, Chunfa Jie, Masayuki Nakamura, Ricky R. Hirschhorn, Xiaofang Wang, Wanli W. Smith, Tsonwin Hai, Michelle A. Poirier, Christopher A. Ross

Research output: Contribution to journalArticle

Abstract

Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine expansion near the N-terminus of huntingtin. The mechanisms of polyglutamine neurotoxicity, and cellular responses are not fully understood. We have studied gene expression profiles by short oligo array using an inducible PC12 cell model expressing an N-terminal huntingtin fragment with expanded polyglutamine (Htt-N63-148Q). Mutant huntingtin Htt-N63 induced cell death and increased the mRNA and protein levels of activating transcription factor 3 (ATF3). Mutant Htt-N63 also significantly enhanced ATF3 transcriptional activity by a promoter-based reporter assay. Overexpression of ATF3 protects against mutant Htt-N63 toxicity and knocking down ATF3 expression reduced Htt-N63 toxicity in a stable PC12 cell line. These results indicated that ATF3 plays a critical role in toxicity induced by mutant Htt-N63 and may lead to a useful therapeutic target.

Original languageEnglish (US)
Pages (from-to)221-229
Number of pages9
JournalBrain research
Volume1286
DOIs
StatePublished - Aug 25 2009

Keywords

  • Activating transcription factor 3
  • Cell death
  • Huntington's disease
  • Mutant huntingtin
  • Polyglutamine

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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