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Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases
Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CM...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Pub. Group
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506996/ https://www.ncbi.nlm.nih.gov/pubmed/26138142 http://dx.doi.org/10.1038/ncomms8520 |
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author | Niehues, Sven Bussmann, Julia Steffes, Georg Erdmann, Ines Köhrer, Caroline Sun, Litao Wagner, Marina Schäfer, Kerstin Wang, Guangxia Koerdt, Sophia N. Stum, Morgane RajBhandary, Uttam L. Thomas, Ulrich Aberle, Hermann Burgess, Robert W. Yang, Xiang-Lei Dieterich, Daniela Storkebaum, Erik |
author_facet | Niehues, Sven Bussmann, Julia Steffes, Georg Erdmann, Ines Köhrer, Caroline Sun, Litao Wagner, Marina Schäfer, Kerstin Wang, Guangxia Koerdt, Sophia N. Stum, Morgane RajBhandary, Uttam L. Thomas, Ulrich Aberle, Hermann Burgess, Robert W. Yang, Xiang-Lei Dieterich, Daniela Storkebaum, Erik |
author_sort | Niehues, Sven |
collection | PubMed |
description | Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNA(Gly) aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT. |
format | Online Article Text |
id | pubmed-4506996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Nature Pub. Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-45069962015-07-21 Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases Niehues, Sven Bussmann, Julia Steffes, Georg Erdmann, Ines Köhrer, Caroline Sun, Litao Wagner, Marina Schäfer, Kerstin Wang, Guangxia Koerdt, Sophia N. Stum, Morgane RajBhandary, Uttam L. Thomas, Ulrich Aberle, Hermann Burgess, Robert W. Yang, Xiang-Lei Dieterich, Daniela Storkebaum, Erik Nat Commun Article Dominant mutations in five tRNA synthetases cause Charcot–Marie–Tooth (CMT) neuropathy, suggesting that altered aminoacylation function underlies the disease. However, previous studies showed that loss of aminoacylation activity is not required to cause CMT. Here we present a Drosophila model for CMT with mutations in glycyl-tRNA synthetase (GARS). Expression of three CMT-mutant GARS proteins induces defects in motor performance and motor and sensory neuron morphology, and shortens lifespan. Mutant GARS proteins display normal subcellular localization but markedly reduce global protein synthesis in motor and sensory neurons, or when ubiquitously expressed in adults, as revealed by FUNCAT and BONCAT. Translational slowdown is not attributable to altered tRNA(Gly) aminoacylation, and cannot be rescued by Drosophila Gars overexpression, indicating a gain-of-toxic-function mechanism. Expression of CMT-mutant tyrosyl-tRNA synthetase also impairs translation, suggesting a common pathogenic mechanism. Finally, genetic reduction of translation is sufficient to induce CMT-like phenotypes, indicating a causal contribution of translational slowdown to CMT. Nature Pub. Group 2015-07-03 /pmc/articles/PMC4506996/ /pubmed/26138142 http://dx.doi.org/10.1038/ncomms8520 Text en Copyright © 2015, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Niehues, Sven Bussmann, Julia Steffes, Georg Erdmann, Ines Köhrer, Caroline Sun, Litao Wagner, Marina Schäfer, Kerstin Wang, Guangxia Koerdt, Sophia N. Stum, Morgane RajBhandary, Uttam L. Thomas, Ulrich Aberle, Hermann Burgess, Robert W. Yang, Xiang-Lei Dieterich, Daniela Storkebaum, Erik Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title | Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title_full | Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title_fullStr | Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title_full_unstemmed | Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title_short | Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases |
title_sort | impaired protein translation in drosophila models for charcot–marie–tooth neuropathy caused by mutant trna synthetases |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506996/ https://www.ncbi.nlm.nih.gov/pubmed/26138142 http://dx.doi.org/10.1038/ncomms8520 |
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