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J Biol Chem. 2016 Feb 12;291(7):3531-40. doi: 10.1074/jbc.M115.675488. Epub 2015 Dec 23.

Regulation of Histone Acetylation by Autophagy in Parkinson Disease.

Author information

1
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.
2
the State Key Laboratory of Medical Genetics, Xiangya Medical School, Central South University, Hunan 410078, China, and.
3
the Sanford-Burnham Medical Research Institute, La Jolla, California 92037.
4
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.
5
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.

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.

KEYWORDS:

epigenetics; histone acetylation; histone deacetylase (HDAC); neurodegenerative disease; neurotoxin

PMID:
26699403
PMCID:
PMC4751393
DOI:
10.1074/jbc.M115.675488
[Indexed for MEDLINE]
Free PMC Article

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