Targeting m 6 A mRNA demethylase FTO alleviates manganese-induced cognitive memory deficits in mice

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 ass...

Full description

Saved in:
Bibliographic Details
Published in:Journal of hazardous materials 2024-09, Vol.476, p.134969
Main Authors: Wen, Yi, Fu, Zhushan, Li, Jiashuo, Liu, Mingyue, Wang, Xinmiao, Chen, Jingqi, Chen, Yue, Wang, Haocheng, Wen, Sihang, Zhang, Ke, Deng, Yu
Format: Article
Language:English
Subjects:
Adenosine - analogs & derivatives
Adenosine - metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO - metabolism
Animals
Cognitive Dysfunction - chemically induced
Cognitive Dysfunction - genetics
Hippocampus - drug effects
Hippocampus - metabolism
Male
Manganese - toxicity
Memory Disorders - chemically induced
Memory Disorders - drug therapy
Memory Disorders - genetics
Memory Disorders - metabolism
Mice
Mice, Inbred C57BL
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - metabolism
Neurons - drug effects
Neurons - metabolism
SOXB1 Transcription Factors - genetics
SOXB1 Transcription Factors - metabolism
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 m A 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.
ISSN:1873-3336