Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China.
Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China.
J Hazard Mater. 2022 Mar 15;426:128099. doi: 10.1016/j.jhazmat.2021.128099. Epub 2021 Dec 23.
One of the major environmental factors that induce PD is Manganese (Mn). Cellular and molecular mechanism of parkinsonism caused by Mn has not been explored clearly. The results of in vivo and in vitro experiments showed that Mn exposure caused abnormal projection of dopaminergic neurons and decreased mRNA expression and protein levels of FTO. This is due to Mn-induced the upregulation of Foxo3a. Using the cell model of overexpression of FTO, we found that FTO could antagonize Mn-induced the down-regulation of axon guidance molecule ephrin-B2 through RNA-seq, MeRIP-qPCR, and RT-qPCR experiments. Through RIP-seq and actinomycin D experiments, it was found that FTO can up-regulate the mRNA mA level of ephrin-B2, which can be recognized by YTHDF2 and degraded. Finally, it is proved that Mn induces dopaminergic neurons projection injury and motor dysfunction through Foxo3a/FTO/mA/ephrin-B2/YTHDF2 signal pathway.
导致帕金森病的主要环境因素之一是锰 (Mn)。锰引起帕金森病的细胞和分子机制尚未得到明确探索。体内和体外实验的结果表明，锰暴露导致多巴胺能神经元的异常投射，并降低 FTO 的 mRNA 表达和蛋白水平。这是由于 Mn 诱导 Foxo3a 的上调。使用 FTO 过表达的细胞模型，我们发现 FTO 可以通过 RNA-seq、MeRIP-qPCR 和 RT-qPCR 实验拮抗 Mn 诱导的轴突导向分子 Ephrin-B2 的下调。通过 RIP-seq 和放线菌素 D 实验，发现 FTO 可以上调 Ephrin-B2 的 mRNA mA 水平，该水平可被 YTHDF2 识别并降解。最后，证明 Mn 通过 Foxo3a/FTO/mA/ephrin-B2/YTHDF2 信号通路诱导多巴胺能神经元投射损伤和运动功能障碍。
