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Science ; 373(6559): 1156-1161, 2021 Sep 03.
Article in English | MEDLINE | ID: mdl-34516839

ABSTRACT

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 type­specific 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.


Subject(s)
Charcot-Marie-Tooth Disease/metabolism , Glycine-tRNA Ligase/metabolism , Protein Serine-Threonine Kinases/metabolism , Stress, Physiological , Tyrosine-tRNA Ligase/metabolism , Activating Transcription Factor 4/genetics , Activating Transcription Factor 4/metabolism , Animals , Charcot-Marie-Tooth Disease/genetics , Charcot-Marie-Tooth Disease/physiopathology , Disease Models, Animal , Female , Gene Deletion , Genes, Dominant , Glycine-tRNA Ligase/genetics , Male , Mice , Mice, Mutant Strains , Motor Neurons/physiology , Protein Biosynthesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/genetics , Spinal Cord/physiopathology , Stress, Physiological/drug effects , Stress, Physiological/genetics , Stress, Physiological/physiology , Transcriptome , Tyrosine-tRNA Ligase/genetics
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