Regulation of Histone Acetylation by Autophagy in Parkinson Disease

Goonho Park,Jieqiong Tan,Guillermina Garcia,Yunyi Kang,Guy Salvesen,Zhuohua Zhang

doi:10.1074/jbc.m115.675488

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.

Highlights

Parkinson disease (PD)2 is pathologically characterized as loss of DA neurons in substantial nigra of midbrain and Lewy body formation in the remaining neurons [1]
PD Environmental Toxins Induce Histone Acetylation—To investigate environmental effects on PD pathogenesis, we first defined a window of time and toxin concentration that resulted in minimal cell morphological changes and cell death using human SH-SY5Y neuroblastoma cells, settling on MPPϩ at 100 ␮M for 7 days
The results suggest that PD-associated environmental toxins aberrantly up-regulate histone expression and induce histone acetylation

Summary

Introduction

Parkinson disease (PD) is pathologically characterized as loss of DA neurons in substantial nigra of midbrain and Lewy body formation in the remaining neurons [1]. Exposure to environmental toxins, such as certain pesticides and herbicides, results in parkinsonism resembling the idiopathic PD [3] Both genetic and environmental factors contribute to PD pathogenesis. Environmental factors are known to cause abnormal epigenetic modifications resulting in human diseases, including neurodegenerative diseases (4 – 6). Such modifications regulate gene expression by mechanisms other than DNA sequence changes [7]. Inhibitors of sirtuin-2 rescues ␣-synuclein-mediated neurotoxicity both in vitro in cell cultures and in vivo in a Drosophila PD model [13] These findings suggest that dysregulation of acetylation of histone or non-histone protein is a common mechanism of neurodegeneration in different neurodegenerative diseases. The results reveal that PD-related environmental toxins regulate autophagy resulting in abnormal histone acetylation to contribute to PD pathogenesis

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