Regulation of Histone Acetylation by Autophagy in Parkinson Disease

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

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.

Publication types

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

MeSH terms

  • Acetylation
  • Aged
  • Animals
  • Autophagy* / drug effects
  • Cell Line
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Enzyme Inhibitors / pharmacology
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects
  • Histone Acetyltransferases / antagonists & inhibitors
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism
  • Histones / metabolism*
  • Humans
  • Male
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism*
  • Mesencephalon / pathology
  • Mice
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / metabolism*
  • Parkinson Disease / enzymology
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Protein Processing, Post-Translational* / drug effects
  • RNA Interference
  • Tissue Banks

Substances

  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Nerve Tissue Proteins
  • Histone Acetyltransferases
  • Histone Deacetylases