运动神经元的m6A图谱调控神经元稳态，FTO抑制可减轻肌萎缩侧索硬化症症状表现。
The motor neuron m6A repertoire governs neuronal homeostasis and FTO inhibition mitigates ALS symptom manifestation.
作者信息
Yen Ya-Ping, Lung Ting-Hsiang, Liau Ee Shan, Wu Chuan-Che, Huang Guan-Lin, Hsu Fang-Yu, Chang Mien, Yang Zheng-Dao, Huang Chia-Yi, Zheng Zhong, Zhao Wei, Hung Jui-Hung, He Chuan, Nie Qing, Chen Jun-An
机构信息
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
Department of Computer Science, National Yang Ming Chiao Tung University, Hsinchu City, Taiwan.
出版信息
Nat Commun. 2025 Apr 30;16(1):4063. doi: 10.1038/s41467-025-59117-2.
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 N-methyladenosine (mA), 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 mA hypomethylation triggers dysregulated expression of high-risk genes associated with ALS and an unforeseen reduction of chromatin accessibility in MNs. Additionally, we observed diminished mA levels in induced pluripotent stem cell derived MNs (iPSCMNs) from familial and sporadic ALS patients. Restoring mA equilibrium via a small molecule or gene therapy significantly preserves MNs from degeneration and mitigates motor impairments in ALS iPSCMNs and murine models. Our study presents a substantial stride towards identifying pioneering efficacious ALS therapies via RNA modifications.
肌萎缩侧索硬化症（ALS）是一种迅速进展且致命的神经退行性疾病，其特征为运动神经元（MNs）退化。在大多数散发性病例中，为何MNs特别易受影响仍不清楚。在此，我们证明了N - 甲基腺苷（mA），一种由METTL3/METTL14甲基转移酶复合物催化的RNA修饰，是ALS发病机制的关键因素。通过在小鼠MNs中条件性敲除Mettl14，我们重现了几乎所有ALS疾病特征。从机制上讲，普遍的mA低甲基化引发了与ALS相关的高风险基因表达失调，以及MNs中染色质可及性意外降低。此外，我们观察到来自家族性和散发性ALS患者的诱导多能干细胞衍生的MNs（iPSCMNs）中mA水平降低。通过小分子或基因疗法恢复mA平衡可显著保护MNs免于退化，并减轻ALS iPSCMNs和小鼠模型中的运动障碍。我们的研究朝着通过RNA修饰确定开创性的有效ALS疗法迈出了重要一步。
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