期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 291, 期 7, 页码 3531-3540出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M115.675488
关键词
epigenetics; histone acetylation; histone deacetylase (HDAC); neurodegenerative disease; neurotoxin
资金
- National Institutes of Health [NS057289]
- Natural Science Foundation of China [313300257, 81429002, 81161120498]
- Ministry of Science and Technology [2011CB51000]
- 111 Program of Foreign Expert Bureau of China [B10036]
- Mogam Science Scholarship Foundation
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.
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