METTL3-mediated m6A RNA methylation was involved in aluminum-induced neurotoxicity
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
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 of Mettl3 gene 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:270 |
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| Enthalten in: |
Ecotoxicology and environmental safety - 270(2024) vom: 15. Jan., Seite 115878 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Yang, Lingling [VerfasserIn] |
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| Links: |
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| Themen: |
63231-63-0 |
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| Anmerkungen: |
Date Completed 23.01.2024 Date Revised 23.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ecoenv.2023.115878 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366413848 |
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| 520 | |a 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 of Mettl3 gene 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Aluminum | |
| 650 | 4 | |a M6A RNA methylation | |
| 650 | 4 | |a METTL3 | |
| 650 | 4 | |a Neurotoxicity | |
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| 650 | 7 | |a Lactates |2 NLM | |
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| 700 | 1 | |a Chen, Liping |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Wenxue |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Guangyu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Bing |e verfasserin |4 aut | |
| 700 | 1 | |a Cen, Yufang |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Huiqi |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Xueqin |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Fangqin |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Yaqin |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Guangzi |e verfasserin |4 aut | |
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