Mettl1-mediated internal m7G methylation of Sptbn2 mRNA elicits neurogenesis and anti-alzheimer’s disease

Abstract

Background N7-methylguanosine (m7G) is one of the most conserved modifications in nucleosides impacting mRNA export, splicing, and translation. However, the precise function and molecular mechanism of internal mRNA m7G methylation in adult hippocampal neurogenesis and neurogenesis-related Alzheimer’s disease (AD) remain unknown. Results We profiled the dynamic Mettl1/Wdr4 expressions and m7G modification during neuronal differentiation of neural stem cells (NSCs) in vitro and in vivo. Adult hippocampal neurogenesis and its molecular mechanisms were examined by morphology, biochemical methods and biological sequencing. The translation efficiency of mRNA was detected by polysome profiling. The stability of Sptbn2 mRNA was constructed by RNA stability assay. APPswe/PS1ΔE9 (APP/PS1) double transgenic mice were used as model of AD. Morris water maze was used to detect the cognitive function. Methods We found that m7G methyltransferase complex Mettl1/Wdr4 as well as m7G was significantly elevated in neurons. Functionally, silencing Mettl1 in neural stem cells (NSCs) markedly decreased m7G modification, neuronal genesis and proliferation in addition to increasing gliogenesis, while forced expression of Mettl1 facilitated neuronal differentiation and proliferation. Mechanistically, the m7G modification of Sptbn2 mRNA by Mettl1 enhanced its stability and translation, which promoted neurogenesis. Importantly, genetic defciency of Mettl1 reduced hippocampal neurogenesis and spatial memory in the adult mice. Furthermore, Mettl1 overexpression in the hippocampus of APP/PS1 mice rescued neurogenesis and behavioral defects. Conclusion Our findings unravel the pivotal role of internal mRNA m7G modification in Sptbn2-mediated neurogenesis, and highlight Mettl3 regulation of neurogenesis as a novel therapeutic target in AD treatment.

Identification and experimental validation of m7G-related molecular subtypes, immune signature, and feature genes in Alzheimer's disease

“…Most m7G regulator genes were downregulated in patients with AD compared with healthy individuals ( DCPS , EIF4E , EIF4E2 , EIF4E3 , LARP1 , METTL1 , NUDT10 , NUDT11 , and SNUPN ). This finding aligns with the results of a recent study where METTL1 was downregulated in AD mice [ 19 ]. The Pearson correlation analysis of 24 m7G regulators genes in the AD datasets suggested that NUDT10 and NUDT11 act synergistically in AD progression.…”

“…Recent research has highlighted the crucial role of m7G methylation in the nervous system and its strong association with the onset and development of various brain diseases [ 14 ], including microcephalic primordial dwarfism [ 15 , 16 ], Down syndrome, ischemic stroke or hypoxia [ 17 ], and multiple sclerosis [ 18 ]. A recent study demonstrated that overexpression of the m7G methyltransferase Mettl1, which is responsible for m7G methylation of internal mRNAs, ameliorated neurogenesis and behavioral defects in APP/PS1 transgenic mice [ 19 ]. This finding highlights the critical role of m7G methylation in AD progression.…”

m1A demethylase Alkbh3 regulates neurogenesis through m1A demethylation of Mmp15 mRNA

“…Herein, our data show that Alkbh3-deficency mice exhibits decreased hippocampal neurogenesis and a severe deficit in spatial learning and memory, suggesting targeting Alkbh3 regulation of neurogenesis as a potential therapeutic strategy for cognitive impairment. Our previous studies also demonstrate that internal mRNA m 7 G modification installed by Mettl1 and/or Mettl3-mediated m 6 A modification facilitate hippocampal neurogenesis [ 18 , 19 ]. We infer whether these epigenetic modifications regulate hippocampal neurogenesis through modifying common gene, thereby improving hippocampal neurogenesis-related cognitive impairment.…”

Epigenetic regulation in adult neural stem cells

“…These findings may need to be tested and confirmed in adult NSCs. Interestingly, ablation of METTL1 inhibits m7G RNA methylation and causes reduced hippocampal neurogenesis from NSCs in adult mice ( Li et al, 2023 ). Therefore, at least some RNA methylation seems to be important for adult NSCs.…”