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

Ya-Ping Yen (), Ting-Hsiang Lung, Ee Shan Liau, Chuan-Che Wu, Guan-Lin Huang, Fang-Yu Hsu, Mien Chang, Zheng-Dao Yang, Chia-Yi Huang, Zhong Zheng, Wei Zhao, Jui-Hung Hung, Chuan He, Qing Nie and Jun-An Chen ()
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Ya-Ping Yen: Academia Sinica
Ting-Hsiang Lung: Academia Sinica
Ee Shan Liau: Academia Sinica
Chuan-Che Wu: Academia Sinica
Guan-Lin Huang: Academia Sinica
Fang-Yu Hsu: Academia Sinica
Mien Chang: Academia Sinica
Zheng-Dao Yang: National Yang Ming Chiao Tung University
Chia-Yi Huang: National Yang Ming Chiao Tung University
Zhong Zheng: University of Chicago
Wei Zhao: University of California, Irvine
Jui-Hung Hung: National Yang Ming Chiao Tung University
Chuan He: University of Chicago
Qing Nie: University of California, Irvine
Jun-An Chen: Academia Sinica

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: Abstract Amyotrophic lateral sclerosis (ALS) is a swiftly progressive and fatal neurodegenerative ailment marked by the degenerative motor neurons (MNs). Why MNs are specifically susceptible in predominantly sporadic cases remains enigmatic. Here, we demonstrated N6-methyladenosine (m6A), an RNA modification catalyzed by the METTL3/METTL14 methyltransferase complex, as a pivotal contributor to ALS pathogenesis. By conditional knockout Mettl14 in murine MNs, we recapitulate almost the full spectrum of ALS disease characteristics. Mechanistically, pervasive m6A hypomethylation triggers dysregulated expression of high-risk genes associated with ALS and an unforeseen reduction of chromatin accessibility in MNs. Additionally, we observed diminished m6A levels in induced pluripotent stem cell derived MNs (iPSC~MNs) from familial and sporadic ALS patients. Restoring m6A equilibrium via a small molecule or gene therapy significantly preserves MNs from degeneration and mitigates motor impairments in ALS iPSC~MNs and murine models. Our study presents a substantial stride towards identifying pioneering efficacious ALS therapies via RNA modifications.

Date: 2025
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DOI: 10.1038/s41467-025-59117-2

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