title: Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology.
abstract: Charcot-Marie-Tooth (CMT) neuropathies are collectively the most common hereditary neurological condition and a major health burden for society. Dominant mutations in the gene GARS, encoding the ubiquitous enzyme, glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and lead to CMT disease type 2D. This genetic disorder exemplifies a recurring motif in neurodegeneration, whereby mutations in essential, widely expressed genes have selective deleterious consequences for the nervous system. Here, using novel Drosophila models, we show a potential solution to this phenomenon. Ubiquitous expression of mutant GlyRS leads to motor deficits, progressive neuromuscular junction (NMJ) denervation and pre-synaptic build-up of mutant GlyRS. Intriguingly, neuronal toxicity is, at least in part, non-cell autonomous, as expression of mutant GlyRS in mesoderm or muscle alone results in similar pathology. This mutant GlyRS toxic gain-of-function, which is WHEP domain-dependent, coincides with abnormal NMJ assembly, leading to synaptic degeneration, and, ultimately, reduced viability. Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene.
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Grice
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
authors.forename: James N
authors.initials: JN
authors.lastname: Sleigh
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA and.
authors.forename: William W
authors.initials: WW
authors.lastname: Motley
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Liu
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
authors.affiliation: Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK, The Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK, zameel.cader@ndcn.ox.ac.uk.
authors.forename: M Zameel
authors.initials: MZ
authors.lastname: Cader
mesh_terms: D000818:Animals; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D005786:Gene Expression Regulation; D006032:Glycine-tRNA Ligase / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D024521:Mushroom Bodies / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology; D009469:Neuromuscular Junction / Q000235:genetics* / Q000254:growth & development / Q000473:pathology; D009830:Olfactory Bulb / Q000473:pathology; D010525:Peripheral Nerves / Q000473:pathology
chemical_list: D006032:Glycine-tRNA Ligase