中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2026, Vol. 21 ›› Issue (6): 2330-2349.doi: 10.4103/NRR.NRR-D-24-01648

• 综述:退行性病与再生 • 上一篇    下一篇

m⁶A RNA 甲基化调节和治疗神经退行性疾病的潜力和策略

  

  • 出版日期:2026-06-15 发布日期:2025-09-18
  • 基金资助:
    国家自然科学基金委员会（一般项目）（82271237、82071218，82230042）；教育部河北医科大学神经病学重点实验室基金（2023001）。

Neuromodulatory role and therapeutic potential of N6 -methyladenosine RNA methylation in neurodegenerative diseases

Jinyu Zhang1, 2, Wenjing Ma1, 2, Ranxu Liu1, 2, Xiaoheng Li2 , Zengqiang Yuan2, *, Jinbo Cheng2, 3, *   

  1. 1 Hengyang Medical School, University of South China, Hengyang, Hunan Province, China;  2 Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, China;  3 Center on Translational Neuroscience, College of Life & Environmental Science, Minzu University of China, Beijing, China
  • Online:2026-06-15 Published:2025-09-18
  • Contact: Jinbo Cheng, PhD, cheng_jinbo@126.com; Zengqiang Yuan, PhD, zqyuan@bmi.ac.cn.
  • Supported by:
    This work was supported by the National Nature Science Foundation of China (General Program), Nos. 82271237, 82071218 (both to JC), and 82230042 (to ZY); the Foundation of Key Laboratory of Neurology, Hebei Medical University, Ministry of Education, China, No. 2023001 (to JC).

摘要：

N⁶-甲基腺苷（m⁶A）RNA甲基化是一种重要的转录后修饰，可动态调节RNA代谢，并在神经元功能中发挥关键作用。逐渐增多的证据表明，m⁶A修饰失调是阿尔茨海默病、帕金森病、多发性硬化症和肌萎缩侧索硬化症等神经退行性疾病的发病机制之一。然而，m⁶A修饰影响这些疾病的确切机制仍不清楚。这篇综述的目的是总结 m⁶A 修饰及其相关调节因子在神经退行性变中的作用，重点关注它们在关键病理过程中的参与过程。在阿尔茨海默病中，m⁶A 修饰导致突触功能障碍、线粒体损伤和神经元凋亡。来自APP/PS1、5XFAD、Tau转基因和果蝇模型的证据表明，METTL3和FTO等调节因子通过神经炎症、circRNA失调和自噬相关机制影响阿尔茨海默病的进展。在帕金森病中，m⁶A调节因子表达的改变通过调节mRNA稳定性和与自噬相关的lncRNA，影响多巴胺能神经元的存活和应激反应。在多发性硬化症和渐冻症中，m⁶A会影响免疫激活、髓鞘修复以及TDP-43等疾病相关基因的调控。除了m⁶A，其他 RNA 甲基化修饰（如 m¹A、m⁵C、m⁷G、尿嘧啶和假尿苷）也通过调节线粒体功能、RNA 代谢和神经元应激反应与神经退行性疾病有关。此外，m⁶A 还具有细胞类型特异性功能：在小胶质细胞中，它调节炎症激活和吞噬功能；在星形胶质细胞中，它调节代谢平衡和谷氨酸相关的神经毒性；在神经元中，它影响突触功能和神经退行性相关基因的表达；在成体神经干细胞中，它控制分化、神经发生和认知可塑性。目前，一些靶向 METTL3 或 FTO 的小分子抑制剂已被开发出来，用于调节 m⁶A 的修饰，为疾病干预提供了新的机会，这表明靶向 m⁶A 相关通路已成为一种很有前景的治疗策略。然而，在优化这些治疗方法的特异性和给药方面仍存在挑战。

https://orcid.org/0000-0002-3627-8544 (Jinbo Cheng); https://orcid.org/0000-0001-5739-2867 (Zengqiang Yuan)

关键词: 阿尔茨海默病, 肌萎缩侧索硬化, 细胞类型, m?A RNA, 甲基化 甲基转移酶样3, 多发性硬化, 神经变性, 神经炎症, 帕金森病, RNA修饰, 治疗策略

Abstract: N6 -methyladenosine RNA methylation, an essential post-transcriptional modification, dynamically regulates RNA metabolism and plays a crucial role in neuronal function. Growing evidence suggests that dysregulated N6 -methyladenosine modification contributes to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis. However, the precise mechanisms by which N6 -methyladenosine modification influences these conditions remain unclear. This review summarizes the role of m6 A modification and its associated regulators in neurodegeneration, focusing on their involvement in key pathological processes. In Alzheimer’s disease, m6 A modification contributes to synaptic dysfunction, mitochondrial damage, and neuronal apoptosis. Evidence from APP/PS1, 5XFAD, tau transgenic, and Drosophila models demonstrates that regulators such as methyltransferase-like 3 and fat mass and obesityassociated protein influence Alzheimer’s disease progression through neuroinflammation, circRNA dysregulation, and autophagy-related mechanisms. In Parkinson’s disease, altered N6 -methyladenosine regulator expression affects dopaminergic neuron survival and stress responses by modulating mRNA stability and autophagy-related lncRNAs. In multiple sclerosis and amyotrophic lateral sclerosis, N6 - methyladenosine affects immune activation, myelin repair, and the regulation of disease-associated genes such as TDP-43. Beyond N6 -methyladenosine, other RNA methylation modifications—such as m1 A, m5 C, m7 G, uracil, and pseudouridine—are implicated in neurodegenerative diseases through their regulation of mitochondrial function, RNA metabolism, and neuronal stress responses. Additionally, N6 - methyladenosine exhibits cell type–specific functions: in microglia, it regulates inflammatory activation and phagocytic function; in astrocytes, it modulates metabolic homeostasis and glutamate-associated neurotoxicity; in neurons, it affects synaptic function and neurodegeneration-related gene expression; and in adult neural stem cells, it controls differentiation, neurogenesis, and cognitive plasticity. Recently, several small-molecule inhibitors targeting methyltransferase-like 3 or fat mass and obesityassociated protein have been developed to modulate N6 -methyladenosine modification, providing new opportunities for disease intervention, with the targeting of N⁶-methyladenosine-related pathways emerging as a promising therapeutic strategy. However, challenges persist in optimizing the specificity and delivery of these therapeutic approaches.

Key words: Alzheimer’s disease, amyotrophic lateral sclerosis, cell type, m6 A RNA methylation, methyltransferase-like 3, multiple sclerosis, neurodegeneration, neuroinflammation, Parkinson’s disease, RNA modification, therapeutic strategy