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

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 pe-ripheral 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. Dis-rupting 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 con-ceptual framework for understanding genetic heterogeneity in light of environmental stress.

复杂疾病往往涉及遗传和环境因素之间的相互作用。2型腓骨肌萎缩症（CMT2）是一组遗传异质性疾病，在这类疾病中，相似的外周神经病理学现象令人费解地是由多种突变基因引起的。它们可能存在的分子联系仍然难以捉摸。在此，我们发现，在环境应激下，许多导致CMT2的突变蛋白会进入应激颗粒（SGs）从而具有相似的特性，在应激颗粒中它们与G3BP发生异常相互作用并整合到SG通路中。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异常结合扰乱了以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脆弱性增加。阻断这种异常相互作用可挽救SG异常并减轻CMT2D小鼠的运动缺陷。这些发现揭示了不同CMT2突变体之间一种依赖应激的分子联系，并为从环境应激角度理解遗传异质性提供了一个概念框架。