Cui Qinqin, Bi Hongyun, Lv Zhanyun, Wu Qigui, Hua Jianfeng, Gu Bokai, Huo Chanjuan, Tang Mingmin, Chen Yanqin, Chen Chongjiu, Chen Sihan, Zhang Xinrui, Wu Zhangrui, Lao Zhengkai, Sheng Nengyin, Shen Chengyong, Zhang Yongdeng, Wu Zhi-Ying, Jin Zhigang, Yang Peiguo, Liu Huaqing, Li Jinsong, Bai Ge
Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 311121, China; NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou 310058, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Cell. 2023 Feb 16;186(4):803-820.e25. doi: 10.1016/j.cell.2022.12.046. Epub 2023 Feb 3.
Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.
复杂疾病通常涉及遗传和环境因素之间的相互作用。2型遗传性运动感觉神经病（CMT2）是一组基因异质性疾病，其中相似的周围神经病理学由各种突变基因莫名引发。它们可能的分子联系仍然难以捉摸。在此，我们发现，在环境应激时，许多导致CMT2的突变蛋白通过进入应激颗粒（SGs）而呈现出相似的特性，在应激颗粒中它们与G3BP异常相互作用并整合到SG途径中。例如，甘氨酰tRNA合成酶（GlyRS）在应激时从细胞质转移到SGs中，突变的GlyRS通过与G3BP异常结合扰乱以G3BP为中心的SG网络。这破坏了SG介导的应激反应，导致运动神经元对应激的易感性增加。破坏这种异常相互作用可挽救CMT2D小鼠的SG异常并减轻运动缺陷。这些发现揭示了不同CMT2突变体之间依赖应激的分子联系，并提供了一个根据环境应激理解基因异质性的概念框架。
