Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases

Sven Niehues, Julia Bussmann, Georg Steffes, Ines Erdmann, Caroline Köhrer, Litao Sun, Marina Wagner, Kerstin Schäfer, Guangxia Wang, Sophia N. Koerdt, Morgane Stum, Sumit Jaiswal, Uttam L. RajBhandary, Ulrich Thomas, Hermann Aberle, Robert W. Burgess, Xiang-Lei Yang, Daniela Dieterich and Erik Storkebaum ()
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Sven Niehues: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Julia Bussmann: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Georg Steffes: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Ines Erdmann: Research Group Neuralomics, Leibniz Institute for Neurobiology
Caroline Köhrer: Massachusetts Institute of Technology
Litao Sun: The Scripps Research Institute
Marina Wagner: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Kerstin Schäfer: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Guangxia Wang: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Sophia N. Koerdt: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Morgane Stum: The Jackson Laboratory
Sumit Jaiswal: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
Uttam L. RajBhandary: Massachusetts Institute of Technology
Ulrich Thomas: Leibniz Institute for Neurobiology
Hermann Aberle: Functional Cell Morphology Lab, Heinrich Heine University
Robert W. Burgess: The Jackson Laboratory
Xiang-Lei Yang: The Scripps Research Institute
Daniela Dieterich: Research Group Neuralomics, Leibniz Institute for Neurobiology
Erik Storkebaum: Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract 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 tRNAGly 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.

Date: 2015
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DOI: 10.1038/ncomms8520

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