Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules

• Published in: Cell 2023-02, Vol.186 (4), p.803-820.e25
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; axon degeneration; Charcot-Marie-Tooth Disease - genetics; Charcot-Marie-Tooth Disease - metabolism; Charcot-Marie-Tooth Disease - pathology; Charcot-Marie-Tooth neuropathies; Cytoplasm; environmental stress; G3BP; genetic heterogeneity; Mice; motor neuron; Motor Neurons; neuromuscular junction; peripheral neuropathy; phase separation; RNA Recognition Motif Proteins - metabolism; stress granule; Stress Granules
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2022.12.046

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. [Display omitted] •Convergence of diverse CMT2-causing mutant proteins in SG•Mutant proteins enter SGs and aberrantly interact with G3BP upon stress•Aberrant G3BP interactions perturb the SG network and cause stress vulnerability•SG-mediated molecular interplay between genetic and environmental pathways Diverse CMT2 neuropathy-causing mutant proteins converge in stress granules, where they aberrantly interact with G3BP and perturb the SG network upon environmental stress.