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

Author

Listed:
  • Sven Niehues

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Julia Bussmann

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Georg Steffes

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Ines Erdmann

    (Research Group Neuralomics, Leibniz Institute for Neurobiology
    Institute for Pharmacology and Toxicology, Otto-von-Guericke-University)

  • Caroline Köhrer

    (Massachusetts Institute of Technology)

  • Litao Sun

    (The Scripps Research Institute)

  • Marina Wagner

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Kerstin Schäfer

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Guangxia Wang

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Sophia N. Koerdt

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • Morgane Stum

    (The Jackson Laboratory)

  • Sumit Jaiswal

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

  • 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
    Institute for Pharmacology and Toxicology, Otto-von-Guericke-University)

  • Erik Storkebaum

    (Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine
    Faculty of Medicine, University of Münster)

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.

Suggested Citation

  • 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, 2015. "Impaired protein translation in Drosophila models for Charcot–Marie–Tooth neuropathy caused by mutant tRNA synthetases," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
  • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8520
    DOI: 10.1038/ncomms8520
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    Cited by:

    1. Salim Megat & Natalia Mora & Jason Sanogo & Olga Roman & Alberto Catanese & Najwa Ouali Alami & Axel Freischmidt & Xhuljana Mingaj & Hortense Calbiac & François Muratet & Sylvie Dirrig-Grosch & Stépha, 2023. "Integrative genetic analysis illuminates ALS heritability and identifies risk genes," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Bob J. Ignacio & Jelmer Dijkstra & Natalia Mora & Erik F. J. Slot & Margot J. Weijsten & Erik Storkebaum & Michiel Vermeulen & Kimberly M. Bonger, 2023. "THRONCAT: metabolic labeling of newly synthesized proteins using a bioorthogonal threonine analog," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Biljana Ermanoska & Bob Asselbergh & Laura Morant & Maria-Luise Petrovic-Erfurth & Seyyedmohsen Hosseinibarkooie & Ricardo Leitão-Gonçalves & Leonardo Almeida-Souza & Sven Bervoets & Litao Sun & LaTas, 2023. "Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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