Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neu...Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology isinexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that uponenvironmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where theyaberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated fromthe cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding toG3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting thisaberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stressdependentmolecular link across diverse CMT2 mutants and provide a conceptual framework for understanding geneticheterogeneity in light of environmental stress.展开更多
Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapie...Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.展开更多
文摘Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology isinexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that uponenvironmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where theyaberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated fromthe cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding toG3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting thisaberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stressdependentmolecular link across diverse CMT2 mutants and provide a conceptual framework for understanding geneticheterogeneity in light of environmental stress.
基金supported by grants from the STI2030-Major Projects(2021ZD0202501)the National Natural Science Foundation of China(NSFC)(82150003,91949104,and 31871022)+1 种基金Zhejiang Province NSFC(LY19H090135),the National Institutes of Health(NIH)(R35 GM139627)Open Project from the State Key Laboratory of Genetic Resources and Evolution of China(GREKF20-08).
文摘Dear Editor,Peripheral neuropathy is a group of devastating diseases affecting periphe-ral nerves and may cause symptoms such as extreme numbness,muscle weakness,and paralysis.Currently,there are no effective therapies for these diseases.Great progress has been made in identifying genetic causes for peripheral neuropathy owing to the advances in genetic testing in the last decade.For example,>100 genes have been identified to be associated with Charcot–Marie–Tooth(CMT)neuropathy,a group of disorders among the most common forms of inherited peripheral neuropathy.
