The transcription factor REST up-regulates tyrosine hydroxylase and antiapoptotic genes and protects dopaminergic neurons against manganese toxicity.

Abstract

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 α, interleukin 1β (IL-1β), IL-6, and interferon γ. 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.

• Authors: Edward Pajarillo, Asha Rizor, Deok-Soo Son, Michael Aschner, Eunsook Lee
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 10 Pg. 3040-3054 (03 06 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32001620 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 Pajarillo et al.

Chemical References

• Interleukin-1beta
• NF-E2-Related Factor 2
• Proto-Oncogene Proteins c-bcl-2
• RE1-silencing transcription factor
• Repressor Proteins
• Tumor Necrosis Factor-alpha
• Manganese
• Heme Oxygenase-1
• Tyrosine 3-Monooxygenase
• CREB-Binding Protein
• Crebbp protein, mouse

Topics

• Animals
• Apoptosis (drug effects)
• Base Sequence
• CREB-Binding Protein (metabolism)
• Dopaminergic Neurons (cytology, drug effects, metabolism)
• Heme Oxygenase-1 (metabolism)
• Interleukin-1beta (metabolism)
• Manganese (toxicity)
• Mice
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• Promoter Regions, Genetic
• Protein Binding
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Repressor Proteins (genetics, metabolism)
• Transcriptional Activation
• Tumor Necrosis Factor-alpha (metabolism)
• Tyrosine 3-Monooxygenase (chemistry, genetics, metabolism)
• Up-Regulation (drug effects)