Down-Regulation of m6A mRNA Methylation Is Involved in Dopaminergic Neuronal Death
Down-Regulation of m6A mRNA Methylation Is Involved in Dopaminergic Neuronal Death
复制标题
m6A mRNA 甲基化的下调与多巴胺能神经元死亡有关
DOI：
10.1021/acschemneuro.8b00657
复制
发表时间：
2019-05-01
影响因子：
5
通讯作者：
Wang, Juan
中科院分区：
文献类型：
--
作者：
Chen, Xuechai;Yu, Chunyu;Wang, Juan
N-6-甲基腺苷（N-6-Methyladenosine，m6 A）是真核生物mRNA中最常见的内部修饰，在转录后调控中起着重要作用。最近的研究强调了m6 A修饰在神经系统中的生物学意义，其失调已被证明与退行性和神经发育疾病有关。帕金森病（PD）是一种常见的年龄相关性神经系统疾病，其发病机制尚未完全阐明。已有报道表明，包括DNA甲基化和组蛋白乙酰化在内的表观遗传机制改变了基因表达，与PD相关。在这项研究中，我们发现，全球m6 A修饰的mRNA下调6-OHDA诱导的PC 12细胞和纹状体的PD大鼠脑。为了进一步探讨PD的相关机制，我们通过过表达m6 A mRNA甲基化和分子核酸去甲基化酶FTO或m6 A抑制剂来降低多巴胺能细胞中m6 A的表达。结果表明，m6 A减少可诱导N-甲基-D-天冬氨酸（NMDA）受体1的表达，增加氧化应激和Ca 2+内流，导致多巴胺能神经元凋亡。总之，m6 A修饰可能在多巴胺能神经元的死亡中起着至关重要的作用，这为理解帕金森病的表观遗传调控提供了一个新的mRNA甲基化视角。
N-6-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 mechanism of PD, we decreased m6A in dopaminergic cells by overexpressing between m6A mRNA methylation and molecular 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.