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METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events
Zhao F, Xu Y, Gao S, Qin L, Austria Q, Siedlak SL, Pajdzik K, Dai Q et al.. Molecular neurodegeneration, 2021-09-30
Topic: Brain proteins, microglia and lab models
Background N6-methyladenosine (m 6 A) modification of RNA influences fundamental aspects of RNA metabolism and m 6 A dysregulation is implicated in various human diseases. In this study, we explored the potential role of RNA m 6 A modification in the pathogenesis of Alzheimer disease (AD). Methods We investigated the m 6 A modification and the expression of m 6 A regulators in the brain tissues of AD patients and determined the impact and underlying mechanism of manipulated expression of m 6 A levels on AD-related deficits both in vitro and in vivo. Results We found decreased neuronal m 6 A levels along with significantly reduced expression of m 6 A methyltransferase like 3 (METTL3) in AD brains. Interestingly, reduced neuronal m 6 A 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 m 6 A 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 m 6 A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.
Key findings
- Results We found decreased neuronal m 6 A levels along with significantly reduced expression of m 6 A methyltransferase like 3 (METTL3) in AD brains.
- Interestingly, reduced neuronal m 6 A 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.
- Conclusions Collectively, these data suggested that METTL3 reduction-mediated m 6 A dysregulation likely contributes to neurodegeneration in AD which may be a therapeutic target for AD.
Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Molecular neurodegeneration) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2021 — within 6 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 34593014) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
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APA 7th
Zhao, F., Xu, Y., Gao, S., Qin, L., Austria, Q., Siedlak, S. L., et al. (2021). METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events. Molecular neurodegeneration. https://doi.org/10.1186/s13024-021-00484-x
Vancouver
Zhao F, Xu Y, Gao S, Qin L, Austria Q, Siedlak SL, et al. METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events. Molecular neurodegeneration. 2021. doi:10.1186/s13024-021-00484-x. PMID: 34593014.
BibTeX
@article{zhao2021-34593014,
author = {Zhao, F. and Xu, Y. and Gao, S. and Qin, L. and Austria, Q. and Siedlak, S. L. and Pajdzik, K. and Dai, Q. and others},
title = {{METTL3-dependent RNA m6A dysregulation contributes to neurodegeneration in Alzheimer's disease through aberrant cell cycle events}},
journal = {Molecular neurodegeneration},
year = {2021},
doi = {10.1186/s13024-021-00484-x},
pmid = {34593014},
url = {https://doi.org/10.1186/s13024-021-00484-x}
}
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