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

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

  • Cell. 2023 Jan 31;S0092-8674(22)01629-4. doi: 10.1016/j.cell.2022.12.046.
Qinqin Cui 1,  Hongyun Bi 1,  Zhanyun Lv 1,  Qigui Wu 2,  Jianfeng Hua 1,  Bokai Gu 1,  Chanjuan Huo 3,  Mingmin Tang 4,  Yanqin Chen 5,  Chongjiu Chen 3,  Sihan Chen 3,  Xinrui Zhang 3,  Zhangrui Wu 3,  Zhengkai Lao 3,  Nengyin Sheng 6,  Chengyong Shen 7,  Yongdeng Zhang 5,  Zhi-Ying Wu 8,  Zhigang Jin 9,  Peiguo Yang 5,  Huaqing Liu 10,  Jinsong Li 11,  Ge Bai 12
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Department of Pharmaceutical Sciences, Zhejiang University City College School of Medicine, Hangzhou 310015, China.
  • 5 School of Life Sciences, Westlake University, Hangzhou 310024, China.
  • 6 State Key Laboratory of Genetic Resources and Evolution, Chinese Academy of Sciences, Kunming 650201, China.
  • 7 Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310020, China.
  • 8 Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou 310009, China.
  • 9 College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004, China.
  • 10 Department of Pharmaceutical Sciences, Zhejiang University City College School of Medicine, Hangzhou 310015, China.
  • 11 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. Electronic address: jsli@sibcb.ac.cn.
  • 12 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. Electronic address: gebai@zju.edu.cn.
PMID: 36738734 DOI: 10.1016/j.cell.2022.12.046
Abstract

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.

Keywords

Charcot-Marie-Tooth neuropathies; G3BP; axon degeneration; environmental stress; genetic heterogeneity; motor neuron; neuromuscular junction; peripheral neuropathy; phase separation; stress granule.

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