Down-Regulation of m6A mRNA Methylation Is Involved in Dopaminergic Neuronal Death

ACS Chem Neurosci. 2019 May 15;10(5):2355-2363. doi: 10.1021/acschemneuro.8b00657. Epub 2019 Mar 14.

Abstract

N6-Methyladenosine (m6A) is the most prevalent internal modification that occurs in the mRNA of eukaryotes and plays a vital role in the post-transcriptional regulation. Recent studies highlighted the biological significance of m6A modification in the nervous system, and its dysregulation has been shown to be related to degenerative and neurodevelopmental diseases. Parkinson's disease (PD) is a common age-related neurological disorder with its pathogenesis still not fully elucidated. Reports have shown that epigenetic mechanisms including DNA methylation and histone acetylation, which alter gene expression, are associated with PD. In this study, we found that global m6A modification of mRNAs is down-regulated in 6-OHDA-induced PC12 cells and the striatum of PD rat brain. To further explore the relationship between m6A mRNA methylation and molecular mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing a nucleic acid demethylase, FTO, or by m6A inhibitor. The results showed that m6A reduction could induce the expression of N-methyl-d-aspartate (NMDA) receptor 1, and elevate oxidative stress and Ca2+ influx, resulting in dopaminergic neuron apoptosis. Collectively, m6A modification may play a vital role in the death of dopaminergic neuron, which provides a novel view of mRNA methylation to understand the epigenetic regulation of Parkinson's disease.

Keywords: 6-methyladenine; FTO; NMDAR1; Parkinson’s disease; mRNA methylation; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / antagonists & inhibitors
  • Adenosine / physiology
  • Animals
  • Apoptosis / physiology
  • Brain / metabolism
  • Cell Death / physiology*
  • Disease Models, Animal
  • Dopaminergic Neurons / physiology*
  • Down-Regulation / physiology
  • Epigenesis, Genetic / physiology
  • Male
  • Methylation
  • Oxidopamine / pharmacology
  • PC12 Cells
  • Parkinson Disease / physiopathology
  • RNA, Messenger / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Sympatholytics / pharmacology

Substances

  • RNA, Messenger
  • Sympatholytics
  • N(6)-methyladenosine
  • Oxidopamine
  • Adenosine