Journal
SCIENCE
Volume 373, Issue 6559, Pages 1156-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.abb3414
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Funding
- National Institutes of Health (NIH) [R37 NS054154, R01 NS113583, U54 OD020351]
- Paul E. Kelly Foundation
- NIH [U54 NS065712-08, F31 NS100328]
- National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre
- European Research Council (ERC) under the European Union [743216]
- Muscular Dystrophy Association [MDA479773]
- EU Joint Programme Neuro-degenerative Disease Research [JPND] [ZonMW 733051075, ZonMW 733051073]
- ERC consolidator grant [ERC-2017-COG 770244]
- Radala Foundation for ALS Research
- Medical Research Council (UK) [MR/N025431/1, MR/V009346/1]
- ERC [309548]
- Newton Fund [MR/N027302/1]
- Evelyn Trust [19/14]
- Lily Foundation
- MRC [MR/S005021/1]
- NIHR Cambridge Biomedical Research Centre [BRC-1215-20014]
- Wellcome Trust [109915/Z/15/Z]
- Wellcome Trust Pathfinder Scheme [201064/Z/16/Z]
- European Research Council (ERC) [309548] Funding Source: European Research Council (ERC)
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Dominant mutations in ubiquitously expressed tRNA synthetase genes lead to peripheral neuropathy through activating the integrated stress response via GCN2 kinase. Inhibiting GCN2 or the ISR may represent a potential therapeutic strategy for CMT.
Dominant mutations in ubiquitously expressed transfer RNA (tRNA) synthetase genes cause axonal peripheral neuropathy, accounting for at least six forms of Charcot-Marie-Tooth (CMT) disease. Genetic evidence in mouse and Drosophila models suggests a gain-of-function mechanism. In this study, we used in vivo, cell type-specific transcriptional and translational profiling to show that mutant tRNA synthetases activate the integrated stress response (ISR) through the sensor kinase GCN2 (general control nonderepressible 2). The chronic activation of the ISR contributed to the pathophysiology, and genetic deletion or pharmacological inhibition of Gcn2 alleviated the peripheral neuropathy. The activation of GCN2 suggests that the aberrant activity of the mutant tRNA synthetases is still related to translation and that inhibiting GCN2 or the ISR may represent a therapeutic strategy in CMT.
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