中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2025, Vol. 20 ›› Issue (6): 1749-1763.doi: 10.4103/NRR.NRR-D-23-01477

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

增强运动皮质中N6-甲基腺苷修饰可促进脊髓损伤后皮质脊髓束的重塑

  

  • 出版日期:2025-06-15 发布日期:2024-11-12

Enhancing m6 A modification in the motor cortex facilitates corticospinal tract remodeling after spinal cord injury

Tian Qin1, 2, 3, #, Yuxin Jin1, 2, 3, #, Yiming Qin1, 2, 3, Feifei Yuan1, 2, 3, Hongbin Lu2, 3, 4, Jianzhong Hu1, 2, 3, *, Yong Cao1, 2, 3, *, Chengjun Li2, 3, 4, *   

  1. 1 Department of Spine Surgery and Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan Province, China;   2 Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Changsha, Hunan Province, China;  3 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China;   4 Department of Sports Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
  • Online:2025-06-15 Published:2024-11-12
  • About author:Jianzhong Hu, PhD, jianzhonghu@csu.edu.cn or jianzhonghu@hotmail.com;Yong Cao, PhD, xycaoyong@csu.edu.cn or caoyong1912@163.com; Chengjun Li, PhD, 443555063@qq.com or lichengjun1992@hotmail.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, Nos. 82030071 (to JH), 82272495 (to YC); Science and Technology Major Project of Changsha, No. kh2103008 (to JH); and Graduate Students’ Independent Innovative Projects of Hunan Province, No. CX20230311 (to YJ).

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摘要：

脊髓损伤常会引起皮质脊髓束的破坏。尽管被破坏的皮质脊髓束具有一定程度的自我更新能力，但其潜在机制尚不清楚。N6-甲基腺苷修饰作为RNA水平上最常见的表观遗传调控形式，已被证明在生物过程中发挥重要作用。然而，N6-甲基腺苷修饰是否参与脊髓损伤后的皮质脊髓束再生仍然未知。此次实验发现脊髓损伤后运动皮质中存在甲基转移酶14高表达，并伴有N6-甲基腺苷水平上调。然后，以慢病毒敲低运动皮质中甲基转移酶14，可见脊髓损伤后皮质脊髓束的再生和神经功能的恢复均显著收到抑制。进一步通过生物信息学分析和RNA甲基化免疫共沉淀-定量PCR分析发现，甲基转移酶14可Mettl14可通过N6-甲基腺苷调控方式上调Trib2的表达，从而激活MAPK通路，促进皮质脊髓束再生。最后研究采用分子对接筛选促进Mettl14稳定性的小分子药物紫丁香苷，并证实灌注紫丁香苷可通过稳定Mettl14促进脊髓损伤小鼠皮质脊髓束的再生和神经功能的恢复。综上，这一研究揭示了N6-甲基腺苷修饰参与脊髓损伤后皮质脊髓束再生的调控机制。

https://orcid.org/0009-0006-7192-5774 (Jianzhong Hu); https://orcid.org/0000-0002-9618-4734 (Yong Cao); 

https://orcid.org/0000-0002-4307-5235 (Chengjun Li)

关键词:

脊髓损伤, N6-甲基腺苷修饰, 表观遗传调控, 甲基转移酶14, 运动皮质, MAPK, TRIB2, 皮质脊髓束重塑, 神经再生, 紫丁香苷

Abstract: Spinal cord injury typically causes corticospinal tract disruption. Although the disrupted corticospinal tract can self-regenerate to a certain degree, the underlying mechanism of this process is still unclear. N6 -methyladenosine (m6 A) modifications are the most common form of epigenetic regulation at the RNA level and play an essential role in biological processes. However, whether m6 A modifications participate in corticospinal tract regeneration after spinal cord injury remains unknown. We found that expression of methyltransferase 14 protein (METTL14) in the locomotor cortex was high after spinal cord injury and accompanied by elevated m6 A levels. Knockdown of Mettl14 in the locomotor cortex was not favorable for corticospinal tract regeneration and neurological recovery after spinal cord injury. Through bioinformatics analysis and methylated RNA immunoprecipitation-quantitative polymerase chain reaction, we found that METTL14 regulated Trib2 expression in an m6 A-regulated manner, thereby activating the mitogen-activated protein kinase pathway and promoting corticospinal tract regeneration. Finally, we administered syringin, a stabilizer of METTL14, using molecular docking. Results confirmed that syringin can promote corticospinal tract regeneration and facilitate neurological recovery by stabilizing METTL14. Findings from this study reveal that m6 A modification is involved in the regulation of corticospinal tract regeneration after spinal cord injury.

Key words: corticospinal tract remodeling, epigenetic regulations, locomotor cortex, m6 A modification, methyltransferase 14 protein (METTL14), mitogen-activated protein kinase, neural regeneration, spinal cord injury, syringin, TRIB2