title: Impaired protein translation in Drosophila models for Charcot-Marie-Tooth neuropathy caused by mutant tRNA synthetases.
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 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.
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Niehues
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bussmann
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Steffes
authors.affiliation: 1] Research Group Neuralomics, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany [2] Institute for Pharmacology and Toxicology, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Erdmann
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Caroline
authors.initials: C
authors.lastname: Köhrer
authors.affiliation: The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Litao
authors.initials: L
authors.lastname: Sun
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Marina
authors.initials: M
authors.lastname: Wagner
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schäfer
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Guangxia
authors.initials: G
authors.lastname: Wang
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Sophia N
authors.initials: SN
authors.lastname: Koerdt
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Morgane
authors.initials: M
authors.lastname: Stum
authors.forename: Sumit
authors.initials: S
authors.lastname: Jaiswal
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Uttam L
authors.initials: UL
authors.lastname: RajBhandary
authors.affiliation: Department of Neurochemistry and Molecular Biology, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Thomas
authors.affiliation: Functional Cell Morphology Lab, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Aberle
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
authors.affiliation: The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Xiang-Lei
authors.initials: XL
authors.lastname: Yang
authors.affiliation: 1] Research Group Neuralomics, Leibniz Institute for Neurobiology, 39118 Magdeburg, Germany [2] Institute for Pharmacology and Toxicology, Otto-von-Guericke-University, 39120 Magdeburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dieterich
authors.affiliation: 1] Molecular Neurogenetics Laboratory, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany [2] Faculty of Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Erik
authors.initials: E
authors.lastname: Storkebaum
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D004195:Disease Models, Animal; D004330:Drosophila; D006032:Glycine-tRNA Ligase / Q000235:genetics*; D006801:Humans; D008017:Life Expectancy; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009068:Movement; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009469:Neuromuscular Junction / Q000473:pathology; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics*; D011984:Sensory Receptor Cells / Q000378:metabolism* / Q000473:pathology; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*
chemical_list: D014448:Tyrosine-tRNA Ligase; D006032:Glycine-tRNA Ligase