Fig. 1: m6A RNA modification levels are downregulated in ALS; loss of m6A methyltransferases METTL3  and METTL14 leads to neurodegeneration. | Nature Communications

Fig. 1: m6A RNA modification levels are downregulated in ALS; loss of m6A methyltransferases METTL3  and METTL14 leads to neurodegeneration.

From: The motor neuron m6A repertoire governs neuronal homeostasis and FTO inhibition mitigates ALS symptom manifestation

Fig. 1: m6A RNA modification levels are downregulated in ALS; loss of m6A methyltransferases METTL3  and METTL14 leads to neurodegeneration.

a Timeline of MN differentiation in control (Ctrl) and ALS (SOD1+/L144F, C9ORF72exp~800 G4C2, TDP43G298S) iPSC lines. CPA (cyclopiazonic acid) was applied to accelerate MN degeneration (annotated as basal time point day 0). NF neurotrophic factors. b–d MN degeneration index and m6A RNA methylation levels of Ctrl and ALS iPSC~MNs. m6A percentages of Ctrl/ALS types at indicated time points were normalized to those at day 0. ALS iPSC~MNs undergo dramatic degeneration from day 7 to day 21 post-CPA treatment, while a significant reduction in m6A level was already exhibited at day 4. The degeneration index measures the neurite fragmentation. e–g Quantification of the m6A ratio in mRNAs from day 4 post-CPA treatment of Ctrl and ALS (SOD1+/L144F, C9ORF72exp~800 G4C2, TDP43G298S) iPSC lines. The mRNAs were extracted by poly(A) purification. The panels at the right show representative images of an m6A dot blot and methylene blue staining (for loading controls) (b–g: n = 3 independent experiments). h Timeline of STM2457 (20 μM)-mediated inhibition of m6A modification during MN differentiation of wild-type iPSC lines. STM2457 was applied for 6 days to accelerate MN degeneration. i and j Inhibition of METTL3-mediated m6A modification in human wild-type iPSC~MNs results in a sharp decline in m6A levels after four days of treatment for STM2457, as assayed by m6A ELISA in mRNA (i) and mRNA m6A dot blot (j) (i, j: n = 3 independent experiments). m6A methylation was normalized to the vehicle (DMSO), which served as a non-stressed control. Note that dramatic neurite degeneration was observed on day 6 in k upon STM2457 treatment. Scale bar, 200 µm. l Quantification of the degeneration index at an indicated time point normalized to the vehicle control (n = 6 independent experiments). Illustrations in a and h created in BioRender. Chen, J. (2025) https://BioRender.com/3nizfu7. All Data are presented as mean ± SD, significant P values from two-tailed t-tests. N.S. non-significant. Source data are provided as a Source data file.

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