2. Academic Validation
  3. Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice

Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice

  • J Hazard Mater. 2024 Jun 18:476:134969. doi: 10.1016/j.jhazmat.2024.134969.
Yi Wen 1,  Zhushan Fu 1,  Jiashuo Li 2,  Mingyue Liu 3,  Xinmiao Wang 1,  Jingqi Chen 1,  Yue Chen 1,  Haocheng Wang 4,  Sihang Wen 1,  Ke Zhang 5,  Yu Deng 6
Affiliations

Affiliations

  • 1 Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, China; Engineering research center of Liaoning Province on environmental health technology and equipment, China Medical University, Shenyang, China.
  • 2 Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, China; Engineering research center of Liaoning Province on environmental health technology and equipment, China Medical University, Shenyang, China; Department of Occupational and Environmental Health, School of Public Health, Shenyang Medical College, Shenyang, China.
  • 3 Department of Developmental Cell Biology, School of Life Sciences, China Medical University, Shenyang, China; Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China.
  • 4 Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States.
  • 5 Department of Developmental Cell Biology, School of Life Sciences, China Medical University, Shenyang, China; Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China. Electronic address: kzhang@cmu.edu.cn.
  • 6 Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China; Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education, China Medical University, Shenyang, China; Engineering research center of Liaoning Province on environmental health technology and equipment, China Medical University, Shenyang, China; Institute of Health Professions Education Assessment and Reform, China Medical University, Shenyang, China. Electronic address: ydeng@cmu.edu.cn.
PMID: 38908185 DOI: 10.1016/j.jhazmat.2024.134969
Abstract

Manganese (Mn) induced learning and memory deficits through mechanisms that are not fully understood. In this study, we discovered that the demethylase FTO was significantly downregulated in hippocampal neurons in an experimental a mouse model of Mn exposure. This decreased expression of FTO was associated with Mn-induced learning and memory impairments, as well as the dysfunction in synaptic plasticity and damage to regional neurons. The overexpression of FTO, or its positive modulation with agonists, provides protection against neurological damage and cognitive impairments. Mechanistically, FTO interacts synergistically with the reader YTHDF3 to facilitate the degradation of GRIN1 and GRIN3B through the m6A modification pathway. Additionally, Mn decreases the phosphorylation of SOX2, which specifically impairs the transcriptional regulation of FTO activity. Additionally, we found that the natural compounds artemisinin and apigenin that can bind molecularly with SOX2 and reduce Mn-induced cognitive dysfunction in mice. Our findings suggest that the SOX2-FTO-Grins axis represents a viable target for addressing Mn-induced neurotoxicity and cognitive impairments.

Keywords

FTO; GRIN; Manganese; N6-methyladenosine; SOX2.

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