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Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia
Cameron R. Miller, Alyssa Ealy, Amanda Gregory, Chelva Janarthanam, William G Albers, Gabriel Richardson, Huajun Jin, Gary D. Zenitsky et al.. Cell Reports, 2025-04-23
Topic: Brain proteins, microglia and lab models
Recent reports suggest dysregulation of the N6-methyladenosine (m6A) RNA modification may contribute to the pathology of neurodegenerative diseases. Herein, we show the m6A methyltransferase complex including METTL3—the catalytic component of the nuclear-localized complex—is robustly upregulated in human microglia and astrocytes exposed to αSyn f and Mn. Subcellular localization studies reveal METTL3 was predominantly cytoplasmic following Mn insult but remained nuclear following αSyn f stimulation in activated microglia. Functional analysis revealed METTL3 and downstream m6A readers, including YTHDF2 and IGF2BP1-3, may regulate the proinflammatory secretome of activated microglia. Notably, methyltransferase activity and m6A abundance were significantly increased following Mn and αSyn f treatment. METTL3 in Mn and αSyn f in vivo models of neuroinflammation, along with human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients, was significantly upregulated. This was further confirmed by single-cell RNA sequencing (scRNA-seq) analysis. Overall, we demonstrate the m6A writer METTL3 may function as a major regulator of chronic neuroinflammation in synucleinopathies.
Key findings
- Functional analysis revealed METTL3 and downstream m6A readers, including YTHDF2 and IGF2BP1-3, may regulate the proinflammatory secretome of activated microglia.
- Notably, methyltransferase activity and m6A abundance were significantly increased following Mn and αSyn f treatment.
- METTL3 in Mn and αSyn f in vivo models of neuroinflammation, along with human postmortem tissues from Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) patients, was significantly upregulated.
- Overall, we demonstrate the m6A writer METTL3 may function as a major regulator of chronic neuroinflammation in synucleinopathies.
Why it matters
This laboratory study found that the m6A writer METTL3 may regulate chronic neuroinflammation in microglia and was increased in models and in brain tissue from people with Alzheimer's, Parkinson's, and dementia with Lewy bodies. It identifies a possible mechanism and target but does not show any treatment or cure for Alzheimer's disease.
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Cell Reports) |
| Journal's citation record | 3 / 4 | Cell Reports: journal h-index 321 (OpenAlex, 2026-10-29) |
| 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 | 4 / 5 | 2025 — within 3 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 | 3 / 7 | Cited 19 times (OpenAlex, 2026-10-10) |
| Citations per year | 2 / 5 | 6.3 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 3 / 6 | Cited 4.9× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 2 / 4 | Cited 19 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Anumantha G. Kanthasamy: h-index 83 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Georgia: institution h-index 904 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40279247) |
| Free to read | 2 / 2 | Free to read |
| Total | 43 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Miller, C. R., Ealy, A., Gregory, A., Janarthanam, C., Albers, W. G., Richardson, G., et al. (2025). Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia. Cell Reports. https://doi.org/10.1016/j.celrep.2025.115618
Vancouver
Miller CR, Ealy A, Gregory A, Janarthanam C, Albers WG, Richardson G, et al. Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia. Cell Reports. 2025. doi:10.1016/j.celrep.2025.115618. PMID: 40279247.
BibTeX
@article{miller2025-40279247,
author = {Miller, Cameron R. and Ealy, Alyssa and Gregory, Amanda and Janarthanam, Chelva and Albers, William G and Richardson, Gabriel and Jin, Huajun and Zenitsky, Gary D. and others},
title = {{Pathological α-synuclein dysregulates epitranscriptomic writer METTL3 to drive neuroinflammation in microglia}},
journal = {Cell Reports},
year = {2025},
doi = {10.1016/j.celrep.2025.115618},
pmid = {40279247},
url = {https://doi.org/10.1016/j.celrep.2025.115618}
}
Studies this one cites
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