Histone deacetylase 6 regulates cytotoxic α-synuclein accumulation through induction of the heat shock response

Yunlan Du, Fei Wang, Jing Zou, Weidong Le, Qing Dong, Zhiying Wang, Fei Shen, Ling Yu, Yansheng Li

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Abnormal aggregation of α-synuclein (α-syn) is central to the pathogenesis of Parkinson's disease (PD). Histone deacetylase 6 (HDAC6) was previously shown to control major cell response pathways to the cytotoxic ubiquitinated aggregates in some protein aggregation diseases. Whether it influences the aggregation process of α-syn in PD models and its related mechanisms are not completely known. Here, we characterized the expression and function of HDAC6 in the ubiquitin-proteasome system impairment-induced PD model. Our results showed that HDAC6 inhibition further exacerbated the nigrostriatal dopamine neurodegeneration and upregulated α-syn oligomers levels, whereas HDAC6 overexpression invitro showed the opposite effects. More importantly, we provided evidence for the first time that HDAC6 regulating α-syn oligomers levels were related to its ability to trigger the heat shock response in a heat shock protein 90-dependent manner. HDAC6 mediated the dissociation of heat shock protein 90-heat shock factor 1-containing complex, and the activation of heat shock factor 1, which led to the expression of major molecular chaperones to prevent the deleterious α-syn aggregation. Thus, we propose that HDAC6 appears as a key modulator of cell protective response to the cytotoxic α-syn aggregates and may serve as a potential target for therapy development in PD.

Original languageEnglish (US)
Pages (from-to)2316-2328
Number of pages13
JournalNeurobiology of Aging
Volume35
Issue number10
DOIs
StatePublished - Oct 2014

Keywords

  • Heat shock
  • Histone deacetylase 6
  • Parkinson's disease
  • Ubiquitin-proteasome system
  • α-synuclein

ASJC Scopus subject areas

  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neuroscience(all)
  • Aging
  • Developmental Biology

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