title: HDAC6 regulates aggresome-autophagy degradation pathway of α-synuclein in response to MPP+-induced stress.
abstract: Increasing evidence suggests that the ubiquitin-binding histone deacetylase-6 (HDAC6) plays an important role in the clearance of misfolded proteins by autophagy. In this study, we treated PC-12 cells over-expressing human mutant (A53T) α-synuclein (α-syn) and SH-SY5Y cells with MPP(+). It was found that HDAC6 expression significantly increased and mainly colocalized with α-syn in the perinuclear region to form aggresome-like bodies. HDAC6 deficiency blocked the formation of aggresome-like bodies and interfered with the autophagy in response to MPP(+)-induced stress. Moreover, misfolded α-syn accumulated into the nuclei, resulting in its reduced clearance, and finally, the number of apoptotic cells significantly increased. Taken together, HDAC6 participated in the degradation of MPP(+)-induced misfolded α-syn aggregates by regulating the aggresome-autophagy pathway. Understanding the mechanism may disclose potential therapeutic targets for synucleinopathies such as Parkinson's disease.
authors.affiliation: Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, China.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.forename: Ji-Jun
authors.initials: JJ
authors.lastname: Shi
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Yang
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Yan-Ling
authors.initials: YL
authors.lastname: Zhang
authors.forename: Jin
authors.initials: J
authors.lastname: Chen
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Hu
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Liu
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000502:physiology*; D006801:Humans; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; C545556:HDAC6 protein, rat; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases; D015655:1-Methyl-4-phenylpyridinium