mA 去甲基化酶 Alkbh3 通过对 Mmp15 mRNA 进行 mA 去甲基化来调节神经发生。

mA demethylase Alkbh3 regulates neurogenesis through mA demethylation of Mmp15 mRNA.

作者信息

Wang Huan, Xie Linjie, Guo Haomin, Li Lishi, Chen Shuwei, Fan Ye, Tian Jingyuan, Xu Liping, Kong Xuejian, Xuan Aiguo

机构信息

Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China.

School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.

出版信息

Cell Biosci. 2024 Jul 14;14(1):92. doi: 10.1186/s13578-024-01275-9.

DOI:10.1186/s13578-024-01275-9

PMID:39004750

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11246583/

Abstract

BACKGROUND

N-Methyladenosine (mA) is an abundant modification of transcripts regulating mRNA structure and translation efficiency. However, the characteristics and biological functions of mRNA mA modification in adult hippocampal neurogenesis remain enigmatic.

RESULTS

We found that mA demethylase Alkbh3 was dramatically enriched in neurons and neuronal genesis. Functionally, depletion of Alkbh3 in neural stem cells (NSCs) significantly decreased mA modification, neuronal differentiation and proliferation coupling with increasing gliogenesis, whereas overexpressing Alkbh3 facilitated neuronal differentiation and proliferation. Mechanistically, the mA demethylation of Mmp15 mRNA by Alkbh3 improved its RNA stability and translational efficacy, which promoted neurogenesis. Therapeutically, the silencing of Alkbh3 reduced hippocampal neurogenesis and impaired spatial memory in the adult mice.

CONCLUSIONS

We reveal a novel function of mA demethylation on Mmp15 mRNA in Alkbh3-mediated neurogenesis, which shed light on advancing Alkbh3 regulation of neurogenesis as a novel neurotherapeutic strategy.

摘要

背景

N-甲基腺苷（mA）是转录本中一种丰富的修饰，可调节mRNA结构和翻译效率。然而，mRNA mA修饰在成体海马神经发生中的特征和生物学功能仍不清楚。

结果

我们发现mA去甲基化酶Alkbh3在神经元和神经发生过程中显著富集。在功能上，神经干细胞（NSCs）中Alkbh3的缺失显著降低了mA修饰、神经元分化和增殖，并伴随着神经胶质生成的增加，而Alkbh3的过表达则促进了神经元分化和增殖。机制上，Alkbh3对Mmp15 mRNA的去甲基化提高了其RNA稳定性和翻译效率，从而促进了神经发生。在治疗方面，Alkbh3的沉默减少了成年小鼠的海马神经发生并损害了空间记忆。