美国加州大学Wang, Yinsheng团队报道了CAG重复RNA中的m1A与TDP-43结合并诱导神经变性。相关研究成果发表在2023年11月8日出版的《自然》。

基因内的微卫星灶重复序列扩增导致许多神经系统疾病。毒性蛋白质和具有重复序列的RNA分子的积累，和/或含有扩增重复序列的核糖核酸分子对核糖核酸结合蛋白的螯合，被认为是疾病病因的重要因素。

该文中，研究人员揭示了CAG重复RNA中的腺苷可以通过TRMT61A甲基化为N1甲基腺苷（m1A），并且m1A可以通过ALKBH3去甲基化。研究人员还观察到，CAG重复RNA中的m1A/腺苷比率随着重复长度的增加而增加，这归因于重复RNA引起的ALKBH3表达减少。此外，TDP-43与RNA中的m1A直接且强烈地结合，这刺激了TDP-43的细胞质错误定位和凝胶状聚集体的形成，类似于在神经疾病中对该蛋白的观察。此外，CAG重复序列RNA中的m1A有助于秀丽隐杆线虫和果蝇CAG重复扩增诱导的神经退行性变。

总之，该研究为核苷酸重复序列扩增导致神经疾病的机制提供了一个新的范式，并揭示了m1A在RNA中的一种新的病理功能。这些发现可能为CAG重复扩增引起的神经退行性疾病的治疗干预提供重要的机制基础。TDP-43与CAG重复RNA上的N1甲基腺苷结合，导致细胞质中形成凝胶状TDP-43聚集体，类似于在神经疾病病理学中观察到的情形。

附：英文原文

Title: m1A in CAG repeat RNA binds to TDP-43 and induces neurodegeneration

Author: Sun, Yuxiang, Dai, Hui, Dai, Xiaoxia, Yin, Jiekai, Cui, Yuxiang, Liu, Xiaochuan, Gonzalez, Gwendolyn, Yuan, Jun, Tang, Feng, Wang, Nan, Perlegos, Alexandra E., Bonini, Nancy M., Yang, X. William, Gu, Weifeng, Wang, Yinsheng

Issue&Volume: 2023-11-08

Abstract: Microsatellite repeat expansions within genes contribute to a number of neurological diseases1,2. The accumulation of toxic proteins and RNA molecules with repetitive sequences, and/or sequestration of RNA-binding proteins by RNA molecules containing expanded repeats are thought to be important contributors to disease aetiology3–9. Here we reveal that the adenosine in CAG repeat RNA can be methylated to N1-methyladenosine (m1A) by TRMT61A, and that m1A can be demethylated by ALKBH3. We also observed that the m1A/adenosine ratio in CAG repeat RNA increases with repeat length, which is attributed to diminished expression of ALKBH3 elicited by the repeat RNA. Additionally, TDP-43 binds directly and strongly with m1A in RNA, which stimulates the cytoplasmic mis-localization and formation of gel-like aggregates of TDP-43, resembling the observations made for the protein in neurological diseases. Moreover, m1A in CAG repeat RNA contributes to CAG repeat expansion-induced neurodegeneration in Caenorhabditis elegans and Drosophila. In sum, our study offers a new paradigm of the mechanism through which nucleotide repeat expansion contributes to neurological diseases and reveals a novel pathological function of m1A in RNA. These findings may provide an important mechanistic basis for therapeutic intervention in neurodegenerative diseases emanating from CAG repeat expansion. TDP-43 binds to N1-methyladenosine on CAG repeat RNA, resulting in the formation of gel-like TDP-43 aggregates in the cytoplasm that resemble those observed in neurological disease pathology.

DOI: 10.1038/s41586-023-06701-5

Source: https://www.nature.com/articles/s41586-023-06701-5