METTL3-mediated m6A RNA methylation was involved in aluminum-induced neurotoxicity.
METTL3-mediated m6A RNA methylation was involved in aluminum-induced neurotoxicity.
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DOI：
10.1016/j.ecoenv.2023.115878
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发表时间：
2023-12
影响因子：
6.8
通讯作者：
Lingling Yang;Liping Chen;Wenxue Li;Yan Zhang;Guangyu Yang;Bing Huang;Yufang Cen;Huiqi Wang-Huiqi
中科院分区：
文献类型：
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作者：
Lingling Yang;Liping Chen;Wenxue Li;Yan Zhang;Guangyu Yang;Bing Huang;Yufang Cen;Huiqi Wang-Huiqi
铝（Al）暴露与多种神经退行性疾病的发展有关。然而，m6 A RNA甲基化是否参与铝诱导的神经毒性仍有待确定。本研究以220 mg/kg的剂量给小鼠灌胃乳酸铝。bw灌胃给药3个月。同时分离原代海马神经元，分别用0、50、100、150 μM乳酸铝处理7天。铝暴露引起神经元萎缩，尼氏体减少，细胞凋亡增加。与此一致，体外研究也表明，铝暴露导致神经细胞凋亡的剂量依赖性的方式，连同m6 A RNA甲基化水平的下降。此外，Mettl 3，Mettl 14，Fto和Ythdf 2的mRNA表达在铝暴露后降低。在铝处理的小鼠和神经元中，胃L3蛋白表达显著下调42%和35%，表明胃L3可能在铝诱导的神经毒性中发挥关键作用。我们建立了Mettl 3基因在海马区特异性过表达的小鼠模型，以证实RNA甲基化的调节作用，发现Mettl 3基因的过表达减轻了铝诱导的神经损伤。整合的MeRIP-seq和RNA-seq分析阐明了631个基因在m6 A RNA甲基化和mRNA表达方面的差异表达。EGFR酪氨酸激酶抑制剂耐药、Rap 1信号通路、蛋白质消化吸收可能参与了铝的神经毒性。此外，VEGFA，Thbs 1和PDGFB可能是中心分子。总的来说，我们的研究结果提供了新的视野到m6 A RNA甲基化在铝诱导的神经退行性疾病中的作用。
Aluminum (Al) exposure has been linked to the development of a variety of neurodegenerative diseases. However, whether m6A RNA methylation participated in Al-induced neurotoxicity remain to be defined. In this study, mice were administrated with aluminum-lactate at dose of 220 mg/kg. bw by gavage for 3 months. Meanwhile, the primary hippocampal neurons were isolated and treated with 0, 50, 100, 150 μM aluminum-lactate, respectively for 7 days. Al exposure caused neuronal shrinkage, decreased Nissl bodies, and increased apoptosis. In accordance, in vitro studies also showed that Al exposure led to neuronal apoptosis in a dose-dependent manner, together with the decline in m6A RNA methylation levels. Moreover, the mRNA expression of Mettl3, Mettl14, Fto, and Ythdf2 were decreased upon Al exposure. Notably, the protein expression of METTL3 was dramatically down-regulated by 42% and 35% in Al-treated mice and neurons, suggesting METTL3 might exert a crucial role in Al-induced neurotoxicity. We next established a mouse model with hippocampus-specific overexpressing ofMettl3gene to confirm the regulatory role of RNA methylation and found that METTL3 overexpression relieved the neurological injury induced by Al. The integrated MeRIP-seq and RNA-seq analysis elucidated that 631 genes were differentially expressed at both m6A RNA methylation and mRNA expression. Notably, EGFR tyrosine kinase inhibitor resistance, Rap1 signaling pathway, protein digestion and absorption might be involved in Al-induced neurotoxicity. Moreover, VEGFA, Thbs1, and PDGFB might be the central molecules. Collectively, our findings provide the novel sight into the role of m6A RNA methylation in neurodegenerative disease induced by Al.