Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

doi:10.1016/j.jhazmat.2021.128099

. 2022 Mar 15:426:128099.

doi: 10.1016/j.jhazmat.2021.128099. Epub 2021 Dec 23.

Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

Zhipeng Qi¹, Shuang Wang², Jiashuo Li³, Yi Wen⁴, Rong Cui⁵, Ke Zhang⁶, Yanan Liu⁷, Xinxin Yang⁸, Lei Zhang⁹, Bin Xu¹⁰, Wei Liu¹¹, Zhaofa Xu¹², Yu Deng¹³

Affiliations

¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: zpqi@cmu.edu.cn.
² Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: wangsh0630@163.com.
³ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: jsli@cmu.edu.cn.
⁴ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: 2020120074@cmu.edu.cn.
⁵ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: cuirong96@163.com.
⁶ 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. Electronic address: kzhang@cmu.edu.cn.
⁷ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China; Department of Preventive Health, Zhuhai People's Hospital, Zhuhai, Guangdong, China. Electronic address: liuyanan@cmu.edu.cn.
⁸ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China; School of Public Health, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: xxyang@cmu.edu.cn.
⁹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: 18447061834@163.com.
¹⁰ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: bxu10@cmu.edu.cn.
¹¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: liuw@cmu.edu.cn.
¹² Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: zfxu@cmu.edu.cn.
¹³ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: dengyu.cmu@163.com.

PMID: 34954437
DOI: 10.1016/j.jhazmat.2021.128099

Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

Zhipeng Qi et al. J Hazard Mater. 2022.

. 2022 Mar 15:426:128099.

doi: 10.1016/j.jhazmat.2021.128099. Epub 2021 Dec 23.

Authors

Zhipeng Qi¹, Shuang Wang², Jiashuo Li³, Yi Wen⁴, Rong Cui⁵, Ke Zhang⁶, Yanan Liu⁷, Xinxin Yang⁸, Lei Zhang⁹, Bin Xu¹⁰, Wei Liu¹¹, Zhaofa Xu¹², Yu Deng¹³

Affiliations

¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: zpqi@cmu.edu.cn.
² Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: wangsh0630@163.com.
³ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: jsli@cmu.edu.cn.
⁴ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: 2020120074@cmu.edu.cn.
⁵ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: cuirong96@163.com.
⁶ 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. Electronic address: kzhang@cmu.edu.cn.
⁷ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China; Department of Preventive Health, Zhuhai People's Hospital, Zhuhai, Guangdong, China. Electronic address: liuyanan@cmu.edu.cn.
⁸ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China; School of Public Health, Xuzhou Medical University, Xuzhou 221004, China. Electronic address: xxyang@cmu.edu.cn.
⁹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: 18447061834@163.com.
¹⁰ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: bxu10@cmu.edu.cn.
¹¹ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: liuw@cmu.edu.cn.
¹² Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: zfxu@cmu.edu.cn.
¹³ Department of Environmental Health, School of Public Health, China Medical University, Shenyang 110122, China. Electronic address: dengyu.cmu@163.com.

PMID: 34954437
DOI: 10.1016/j.jhazmat.2021.128099

Abstract

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 m⁶A 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/m⁶A/ephrin-B2/YTHDF2 signal pathway.

Keywords: Ephrin-B2; FTO; Manganese; Parkinsonism; YTHDF2.

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Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

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Protective role of mRNA demethylase FTO on axon guidance molecules of nigro-striatal projection system in manganese-induced parkinsonism

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