浙江大学白戈等研究人员合作发现，不同的CMT2神经病与应激颗粒中异常的G3BP相互作用有关。相关论文于2023年2月3日在线发表在《细胞》杂志上。
研究人员发现，在环境胁迫下，许多导致Charcot-Marie-Tooth 2型神经病（CMT2）突变的蛋白通过进入应激颗粒（SG）而具有相似的性质，其中它们与G3BP异常相互作用并整合到SG通路中。例如，glycyl-tRNA合成酶（GlyRS）在应激时从细胞质转移到SG，突变的GlyRS通过异常与G3BP结合而扰乱G3BP-中央SG网络。这破坏了SG介导的应激反应，导致运动神经元应激易感性增加。在CMT2D小鼠中，破坏这种异常的相互作用可以挽救SG异常并缓解运动缺陷。这些发现揭示了不同CMT2突变体之间的胁迫依赖分子链接，并为理解环境胁迫下的遗传异质性提供了一个概念框架。
据介绍，复杂的疾病往往涉及遗传和环境因素之间的相互作用。CMT2是一类遗传异质性疾病，其中相似的周围神经病理是由变异突变的基因引起的。它们之间可能的分子联系仍不清楚。
附：英文原文
Title: Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules
Author: Qinqin Cui, Hongyun Bi, Zhanyun Lv, Qigui Wu, Jianfeng Hua, Bokai Gu, Chanjuan Huo, Mingmin Tang, Yanqin Chen, Chongjiu Chen, Sihan Chen, Xinrui Zhang, Zhangrui Wu, Zhengkai Lao, Nengyin Sheng, Chengyong Shen, Yongdeng Zhang, Zhi-Ying Wu, Zhigang Jin, Peiguo Yang, Huaqing Liu, Jinsong Li, Ge Bai
Issue&Volume: 2023-02-03
Abstract: Complex diseases often involve the interplay between genetic and environmental factors.Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneousdisorders, in which similar peripheral neuropathology is inexplicably caused by variousmutated genes. Their possible molecular links remain elusive. Here, we found thatupon environmental stress, many CMT2-causing mutant proteins adopt similar propertiesby entering stress granules (SGs), where they aberrantly interact with G3BP and integrateinto SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated fromthe cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centricSG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses,leading to increased stress vulnerability in motoneurons. Disrupting this aberrantinteraction rescues SG abnormalities and alleviates motor deficits in CMT2D mice.These findings reveal a stress-dependent molecular link across diverse CMT2 mutantsand provide a conceptual framework for understanding genetic heterogeneity in lightof environmental stress.
DOI: 10.1016/j.cell.2022.12.046
Source: https://www.cell.com/cell/fulltext/S0092-8674(22)01629-4