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

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.