The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy

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 models suggests a gain-of-function mechanism. In this study, we used in vivo, ce...

Full description

Saved in:

Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 373; no. 6559; pp. 1156 - 1161
Main Authors:	Spaulding, E L, Hines, T J, Bais, P, Tadenev, A L D, Schneider, R, Jewett, D, Pattavina, B, Pratt, S L, Morelli, K H, Stum, M G, Hill, D P, Gobet, C, Pipis, M, Reilly, M M, Jennings, M J, Horvath, R, Bai, Y, Shy, M E, Alvarez-Castelao, B, Schuman, E M, Bogdanik, L P, Storkebaum, E, Burgess, R W
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 03-09-2021
Subjects:	Activating Transcription Factor 4 - genetics Activating Transcription Factor 4 - metabolism Animal models Animals Cellular stress response Charcot-Marie-Tooth disease Charcot-Marie-Tooth Disease - genetics Charcot-Marie-Tooth Disease - metabolism Charcot-Marie-Tooth Disease - physiopathology Codons Disease Models, Animal Female Gene Deletion Gene expression Genes, Dominant Genetics Glycine Glycine-tRNA Ligase - genetics Glycine-tRNA Ligase - metabolism In vivo methods and tests Kinases Male Mice Mice, Mutant Strains Motor Neurons - physiology Mutants Mutation Pathophysiology Peripheral neuropathy Protein Biosynthesis Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Protein Serine-Threonine Kinases - antagonists & inhibitors Protein Serine-Threonine Kinases - genetics Protein Serine-Threonine Kinases - metabolism Protein synthesis Proteins Ribonucleic acid Ribosomes RNA Spinal cord Spinal Cord - physiopathology Stalling Stress, Physiological - drug effects Stress, Physiological - genetics Stress, Physiological - physiology Transcription Transcriptome Transfer RNA tRNA Tyrosine-tRNA Ligase - genetics Tyrosine-tRNA Ligase - metabolism
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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 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 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Current address: Mount Desert Island Biological Laboratory, Bar Harbor, ME 04609 USA Current address: Department of Biochemistry, Veterinary School, University Complutense of Madrid, Madrid, Spain Author contributions: ELS, RS, DJ, BP and LPB performed in vivo experiments; PB and DPH analyzed transcriptome data; TJH, ALDT, SP performed ISR activation studies; KHM and MGS generated mouse models; CG performed codon usage analysis; MP, MMR, MJJ, RH, YB and MES provided patient samples and analyses; BA-C and EMS provided mice prior to publication, ELS and RWB oversaw experimental design and data analysis and wrote the manuscript with input from all authors.
ISSN:	0036-8075 1095-9203 1095-9203
DOI:	10.1126/science.abb3414