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Regulation of Histone Acetylation by Autophagy in Parkinson Disease.
J Biol Chem. 2016 Feb 12; 291(7):3531-40.JB

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+Show Affiliations

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.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.the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.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.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26699403

Citation

Park, Goonho, et al. "Regulation of Histone Acetylation By Autophagy in Parkinson Disease." The Journal of Biological Chemistry, vol. 291, no. 7, 2016, pp. 3531-40.
Park G, Tan J, Garcia G, et al. Regulation of Histone Acetylation by Autophagy in Parkinson Disease. J Biol Chem. 2016;291(7):3531-40.
Park, G., Tan, J., Garcia, G., Kang, Y., Salvesen, G., & Zhang, Z. (2016). Regulation of Histone Acetylation by Autophagy in Parkinson Disease. The Journal of Biological Chemistry, 291(7), 3531-40. https://doi.org/10.1074/jbc.M115.675488
Park G, et al. Regulation of Histone Acetylation By Autophagy in Parkinson Disease. J Biol Chem. 2016 Feb 12;291(7):3531-40. PubMed PMID: 26699403.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Regulation of Histone Acetylation by Autophagy in Parkinson Disease. AU - Park,Goonho, AU - Tan,Jieqiong, AU - Garcia,Guillermina, AU - Kang,Yunyi, AU - Salvesen,Guy, AU - Zhang,Zhuohua, Y1 - 2015/12/23/ PY - 2015/06/28/received PY - 2015/12/25/entrez PY - 2015/12/25/pubmed PY - 2016/7/7/medline KW - epigenetics KW - histone acetylation KW - histone deacetylase (HDAC) KW - neurodegenerative disease KW - neurotoxin SP - 3531 EP - 40 JF - The Journal of biological chemistry JO - J Biol Chem VL - 291 IS - 7 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/26699403/Regulation_of_Histone_Acetylation_by_Autophagy_in_Parkinson_Disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)45172-5 DB - PRIME DP - Unbound Medicine ER -