title: Histone deacetylase 6 regulates cytotoxic α-synuclein accumulation through induction of the heat shock response.
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 in vitro 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.
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yunlan
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zou
authors.affiliation: Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Le
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Shen
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: lliyans@hotmail.com.
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010300:Parkinson Disease / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D066263:Protein Aggregation, Pathological; D014157:Transcription Factors / Q000378:metabolism*; D054875:Ubiquitination; D051844:alpha-Synuclein / Q000378:metabolism* / Q000633:toxicity
chemical_list: D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; C490017:Hsf1 protein, mouse; D018832:Molecular Chaperones; D014157:Transcription Factors; D051844:alpha-Synuclein; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Heat shock; Histone deacetylase 6; Parkinson's disease; Ubiquitin-proteasome system; α-synuclein