Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 10, Pages 3040-3054Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA119.011446
Keywords
manganese; Parkinson disease; neurodegeneration; neurodegenerative disease; neurotoxin; dopaminergic neurons; neuron restrictive silencer factor (NRSF); neurotoxicity; RE1-silencing transcription factor (REST); Tyrosine Hydroxylase
Categories
Funding
- National Institutes of Health Research [R01 ES024756, U54 MD007582, NCI SC1 CA200519, R01 ES10563, R01 ES07331, 1R21 ES025415]
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Dopaminergic functions are important for various biological activities, and their impairment leads to neurodegeneration, a hallmark of Parkinson's disease (PD). Chronic manganese (Mn) exposure causes the neurological disorder manganism, presenting symptoms similar to those of PD. Emerging evidence has linked the transcription factor RE1-silencing transcription factor (REST) to PD and also Alzheimer's disease. But REST's role in dopaminergic neurons is unclear. Here, we investigated whether REST protects dopaminergic neurons against Mn-induced toxicity and enhances expression of the dopamine-synthesizing enzyme tyrosine hydroxylase (TH). We report that REST binds to RE1 consensus sites in the TH gene promoter, stimulates TH transcription, and increases TH mRNA and protein levels in dopaminergic cells. REST binding to the TH promoter recruited the epigenetic modifier cAMP-response element-binding protein?binding protein/p300 and thereby up-regulated TH expression. REST relieved Mn-induced repression of TH promoter activity, mRNA, and protein levels and also reduced Mn-induced oxidative stress, inflammation, and apoptosis in dopaminergic neurons. REST reduced Mn-induced proinflammatory cytokines, including tumor necrosis factor ?, interleukin 1? (IL-1?), IL-6, and interferon ?. Moreover, REST inhibited the Mn-induced proapoptotic proteins Bcl-2?associated X protein (Bax) and death-associated protein 6 (Daxx) and attenuated an Mn-induced decrease in the antiapoptotic proteins Bcl-2 and Bcl-xL. REST also enhanced the expression of antioxidant proteins, including catalase, NF-E2?related factor 2 (Nrf2), and heme oxygenase 1 (HO-1). Our findings indicate that REST activates TH expression and thereby protects neurons against Mn-induced toxicity and neurological disorders associated with dopaminergic neurodegeneration.
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