title: Regulation of Histone Acetylation by Autophagy in Parkinson Disease.
abstract: Parkinson disease (PD) is the most common age-dependent neurodegenerative movement disorder. Accumulated evidence indicates both environmental and genetic factors play important roles in PD pathogenesis, but the potential interaction between environment and genetics in PD etiology remains largely elusive. Here, we report that PD-related neurotoxins induce both expression and acetylation of multiple sites of histones in cultured human cells and mouse midbrain dopaminergic (DA) neurons. Consistently, levels of histone acetylation are markedly higher in midbrain DA neurons of PD patients compared to those of their matched control individuals. Further analysis reveals that multiple histone deacetylases (HDACs) are concurrently decreased in 1-methyl-4-phenylpyridinium (MPP(+))-treated cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse brains, as well as midbrain tissues of human PD patients. Finally, inhibition of histone acetyltransferase (HAT) protects, whereas inhibition of HDAC1 and HDAC2 potentiates, MPP(+)-induced cell death. Pharmacological and genetic inhibition of autophagy suppresses MPP(+)-induced HDACs degradation. The study reveals that PD environmental factors induce HDACs degradation and histone acetylation increase in DA neurons via autophagy and identifies an epigenetic mechanism in PD pathogenesis.
authors.affiliation: From the Graduate Program of Biomedical Science, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, the University of California, San Diego, La Jolla, California 92037.
authors.forename: Goonho
authors.initials: G
authors.lastname: Park
authors.affiliation: the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Hunan 410078, China, and.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Tan
authors.affiliation: the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Garcia
authors.affiliation: the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Yunyi
authors.initials: Y
authors.lastname: Kang
authors.affiliation: From the Graduate Program of Biomedical Science, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
authors.forename: Guy
authors.initials: G
authors.lastname: Salvesen
authors.affiliation: From the Graduate Program of Biomedical Science, Sanford-Burnham Medical Research Institute, La Jolla, California 92037, the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Hunan 410078, China, and the Sanford-Burnham Medical Research Institute, La Jolla, California 92037 zhangzhuohua@sklmg.edu.cn.
authors.forename: Zhuohua
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000107:Acetylation; D000368:Aged; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D034622:RNA Interference; D014015:Tissue Banks
chemical_list: D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases
keywords: epigenetics; histone acetylation; histone deacetylase (HDAC); neurodegenerative disease; neurotoxin