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Targeting m6A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice
Yi Wen1, Zhushan Fu1, Jiashuo Li2
1Department 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.
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.
Insights
Manganese exposure impairs learning and memory by reducing FTO demethylase activity in the brain. Restoring FTO levels or using compounds like artemisinin protects against this neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Manganese (Mn) exposure is linked to learning and memory deficits, but the underlying mechanisms remain unclear.
- Understanding Mn neurotoxicity is crucial for developing effective interventions.
- Identifying molecular targets affected by Mn is a key research area.
Purpose of the Study:
- To investigate the role of the FTO demethylase in manganese-induced cognitive impairment.
- To elucidate the molecular mechanisms by which Mn affects FTO and neuronal function.
- To explore potential therapeutic strategies targeting the identified pathways.
Main Methods:
- Utilized a mouse model of Mn exposure.
- Assessed learning and memory using behavioral tests.
- Analyzed FTO expression and its interaction with YTHDF3 in hippocampal neurons.
- Investigated the effect of FTO modulation and natural compounds (artemisinin, apigenin) on Mn-induced neurotoxicity.
Main Results:
- Manganese exposure significantly downregulated FTO demethylase in hippocampal neurons, correlating with cognitive deficits.
- FTO downregulation impaired synaptic plasticity and caused neuronal damage.
- Overexpressing FTO or using FTO agonists protected against Mn-induced neurological and cognitive impairments.
- Mn exposure decreased SOX2 phosphorylation, impairing FTO transcriptional regulation.
- Artemisinin and apigenin mitigated Mn-induced cognitive dysfunction by interacting with SOX2.
Conclusions:
- The SOX2-FTO-Grins axis is implicated in Mn-induced neurotoxicity and cognitive impairments.
- Targeting FTO or modulating the SOX2 pathway shows therapeutic potential for Mn-related neurological disorders.
- Natural compounds like artemisinin and apigenin may offer protective effects against Mn neurotoxicity.
