m6A去甲基化酶FTO調節亞砷酸鹽引起的多巴胺能神經傳遞缺陷

2018年6月，重慶醫科大學公共衛生與管理學院；職業與環境衛生系；醫學與社會發展研究中心；衛生領域社會風險治理創新中心；重慶醫科大學生命科學研究所；重慶醫科大學護理學院護理科學博士后流動站；重慶醫科大學**附屬醫院神經內科，重慶市神經病學重點實驗室，重慶醫科大學**附屬醫院藥劑科；公共衛生實驗教學中心；重慶醫科大學組織細胞生物學實驗室；實驗教學與管理中心 (Department of Occupational and Environmental Health, School of Public Health and Management, Research Center for Medicine and Social Development, Innovation Center for Social Risk Governance in Health, Chongqing Medical University, Chongqing, People’s Republic of China；Institute of Life Sciences, Chongqing Medical University,Chongqing, People’s Republic of China; and Post-doctoral Research Stations of Nursing Science, School of Nursing, Chongqing Medical University, Chongqing, People’s Republic of China;      Chongqing Key Laboratory of Neurology, Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China；Department of Pharmacy, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China；Center of Experimental Teaching for Public Health; and kjLaboratory of Tissue and Cell Biology, Experimental Teaching and Management Center,Chongqing Medical University, Chongqing, People’s Republic of China) Chengzhi Chen老師研究團隊在《TOXICOLOGICAL SCIENCES》上發表論文：

“m6A Demethylase FTO Regulates Dopaminergic Neurotransmission Deficits Caused by Arsenite”

“m6A去甲基化酶FTO調節亞砷酸鹽引起的多巴胺能神經傳遞缺陷”

Abstract：

Arsenite exposure is known to increase the risk of neurological disorders via alteration of dopamine content, but the detailed molecular mechanisms remain largely unknown. In this study, using both dopaminergic neurons of the PC-12 cell line and C57BL/6J mice as in vitro and in vivo models, our results demonstrated that 6 months of arsenite exposure via drinking water caused significant learning and memory impairment, anxiety-like behavior and alterations in conditioned avoidance and escape responses in male adult mice. We also were the first to reveal that the reduction in dopamine content induced by arsenite mainly resulted from deficits in dopaminergic neurotransmission in the synaptic cleft. The reversible N6- methyladenosine (m6A) modification is a novel epigenetic marker with broad roles in fundamental biological processes. We further evaluated the effect of arsenite on the m6A modification and tested if regulation of the m6A modification by demethylase fat mass and obesity-associated (FTO) could affect dopaminergic neurotransmission. Our data demonstrated for the first time that arsenite remarkably increased m6A modification, and FTO possessed the ability to alleviate the deficits in dopaminergic neurotransmission in response to arsenite exposure. Our findings not only provide valuable insight into the molecular neurotoxic pathogenesis of arsenite exposure, but are also the first evidence that regulation of FTO may be considered as a novel strategy for the prevention of arsenite-associated neurological disorders.

摘要：

已知接觸亞砷酸鹽會通過改變多巴胺含量而增加神經系統疾病的風險，但詳細的分子機制在很大程度上仍然未知。本研究采用PC-12細胞系和C57BL/6J小鼠的多巴胺能神經元作為體內和體外模型，結果表明，6個月的飲用水亞砷酸鹽暴露會導致雄性成年小鼠明顯的學習和記憶障礙、焦慮樣行為和條件回避和逃避反應的改變。科研人員也**揭示了亞砷酸鹽引起的多巴胺含量減少主要是由于突觸間隙中多巴胺能神經傳遞的缺陷。可逆的N6-甲基腺苷(m6A)修飾是一種新的表觀遺傳標記，在基本生物過程中具有廣泛的作用。科研人員進一步評估了亞砷酸鹽對m6A修飾的影響，并測試了去甲基化酶脂肪質量和肥胖相關(FTO)對m6A修飾的調節是否會影響多巴胺能神經傳遞。科研人員的數據**證明，亞砷酸鹽顯著增加m6A修飾，FTO具有減輕亞砷酸鹽暴露后多巴胺能神經傳遞缺陷的能力。科研人員的發現不僅為亞砷酸鹽暴露的分子神經毒性發病機制提供了有價值的見解，而且也**證明調節FTO可能被認為是預防亞砷酸鹽相關神經系統疾病的新策略。

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