Dataset Information

METTL3-dependent RNA m⁶A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

ABSTRACT:

Background

N6-methyladenosine (m⁶A) modification of RNA influences fundamental aspects of RNA metabolism and m⁶A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m⁶A modification in the pathogenesis of Alzheimer disease (AD).

Methods

We investigated the m⁶A modification and the expression of m⁶A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m⁶A levels on AD-related deficits both in vitro and in vivo.

Results

We found decreased neuronal m⁶A levels along with significantly reduced expression of m⁶A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m⁶A modification in the hippocampus caused by METTL3 knockdown led to significant memory deficits, accompanied by extensive synaptic loss and neuronal death along with multiple AD-related cellular alterations including oxidative stress and aberrant cell cycle events in vivo. Inhibition of oxidative stress or cell cycle alleviated shMettl3-induced apoptotic activation and neuronal damage in primary neurons. Restored m⁶A modification by inhibiting its demethylation in vitro rescued abnormal cell cycle events, neuronal deficits and death induced by METTL3 knockdown. Soluble Aβ oligomers caused reduced METTL3 expression and METTL3 knockdown exacerbated while METTL3 overexpression rescued Aβ-induced synaptic PSD95 loss in vitro. Importantly, METTL3 overexpression rescued Aβ-induced synaptic damage and cognitive impairment in vivo.

Conclusions

Collectively, these data suggested that METTL3 reduction-mediated m⁶A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.

SUBMITTER: Zhao F

PROVIDER: S-EPMC8482683 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Peri‑prosthetic osteolysis (PPO) induced by wear particles is considered the primary cause of titanium prosthesis failure and revision surgery. The specific molecular mechanisms involve titanium particles inducing multiple intracellular pathways, which impact disease prevention and the targeted therapy of PPO. Notably, N6‑methyladenosine (m6A) serves critical roles in epigenetic regulation, particularly in bone metabolism and inflammatory responses. Thus, the present study aimed to determine the role of RNA methylation in titanium particle‑induced osteolysis. Results of reverse transcription‑quantitative PCR (RT‑qPCR), western blotting, ELISA and RNA dot blot assays revealed that titanium particles induced osteogenic inhibition and proinflammatory responses, accompanied by the reduced expression of methyltransferase‑like (Mettl) 3, a key component of m6A methyltransferase. Specific lentiviruses vectors were employed for Mettl3 knockdown and overexpression experiments. RT‑qPCR, western blotting and ELISA revealed that the knockdown of Mettl3 induced osteogenic inhibition and proinflammatory responses comparable with that induced by titanium particle, while Mettl3 overexpression attenuated titanium particle‑induced cellular reactions. Methylated RNA immunoprecipitation‑qPCR results revealed that titanium particles mediated the methylation of two inhibitory molecules, namely Smad7 and SMAD specific E3 ubiquitin protein ligase 1, via Mettl3 in bone morphogenetic protein signaling, leading to osteogenic inhibition. Furthermore, titanium particles induced activation of the nucleotide binding oligomerization domain 1 signaling pathway through methylation regulation, and the subsequent activation of the MAPK and NF‑κB pathways. Collectively, the results of the present study indicated that titanium particles utilized Mettl3 as an upstream regulatory molecule to induce osteogenic inhibition and inflammatory responses. Thus, the present study may provide novel insights into potential therapeutic targets for aseptic loosening in titanium prostheses.

Dataset Information

METTL3-dependent RNA m⁶A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.

Background

Methods

Results

Conclusions

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

METTL3-dependent RNA m⁶A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events.