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

Spaulding, E. L., Hines, T. J., Bais, P., Tadenev, A. L. D., Schneider, R., Jewett, D., et al. (2021). The integrated stress response contributes to tRNA synthetase-associated peripheral neuropathy. Science, 373(6559), 1156-1161. doi:10.1126/science.abb3414.

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 Creators:
Spaulding, E L 1, 2, Author
Hines, T J 1, Author
Bais, P1, Author
Tadenev, A L D 1, Author
Schneider, R1, Author
Jewett, D1, Author
Pattavina, B1, Author
Pratt, S L 1, 3, Author
Morelli, K H 1, 2, Author
Stum, M G 1, Author
Hill , D P 1, Author
Gobet, C4, Author
Pipis, M 5, Author
Reilly , M M5, Author
Jennings, M J 6, Author
Horvath, R 6, Author
Bai, Y7, Author
Shy, M E7, Author
Alvarez-Castelao, B8, Author
Schuman, Erin M.8, Author           
Bogdanik, L P 1, AuthorStorkebaum, E9, AuthorBurgess , R W 1, 2, 3, Author more..
Affiliations:
1The Jackson Laboratory, Bar Harbor, ME 04609, USA, ou_persistent22              
2Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA., ou_persistent22              
3Neuroscience Program, Graduate School of Biomedical Sciences, Tufts University, Boston, MA 02111, USA., ou_persistent22              
4School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland., ou_persistent22              
5MRC Centre for Neuromuscular Diseases, Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK., ou_persistent22              
6Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK., ou_persistent22              
7Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA., ou_persistent22              
8Synaptic Plasticity Department, Max Planck Institute for Brain Research, Max Planck Society, ou_2461710              
9Department of Molecular Neurobiology, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University, Nijmegen, Netherlands., ou_persistent22              

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 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 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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Language(s): eng - English
 Dates: 2020-02-172021-07-162021-09-01
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1126/science.abb3414
PMID: 34516839
 Degree: -

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Project name : ERC-AdG NeuroRibo
Grant ID : 743216
Funding program : Horizon 2020 (H2020)
Funding organization : European Commission (EC)

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Title: Science
  Abbreviation : Science
Source Genre: Journal
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Publ. Info: Washington, D.C. : American Association for the Advancement of Science
Pages: - Volume / Issue: 373 (6559) Sequence Number: - Start / End Page: 1156 - 1161 Identifier: ISSN: 0036-8075
CoNE: https://pure.mpg.de/cone/journals/resource/991042748276600_1