title: CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.
abstract: Aminoacyl-tRNA synthetases are ubiquitously expressed proteins that charge tRNAs with their cognate amino acids. By ensuring the fidelity of protein synthesis, these enzymes are essential for the viability of every cell. Yet, mutations in six tRNA synthetases specifically affect the peripheral nerves and cause Charcot-Marie-Tooth (CMT) disease. The CMT-causing mutations in tyrosyl- and glycyl-tRNA synthetases (YARS and GARS, respectively) alter the activity of the proteins in a range of ways (some mutations do not impact charging function, while others abrogate it), making a loss of function in tRNA charging unlikely to be the cause of disease pathology. It is currently unknown which cellular mechanisms are triggered by the mutant enzymes and how this leads to neurodegeneration. Here, by expressing two pathogenic mutations (G240R, P234KY) in Drosophila, we generated a model for GARS-associated neuropathy. We observed compromised viability, and behavioral, electrophysiological and morphological impairment in flies expressing the cytoplasmic isoform of mutant GARS. Their features recapitulated several hallmarks of CMT pathophysiology and were similar to the phenotypes identified in our previously described Drosophila model of YARS-associated neuropathy. Furthermore, CG8316 and CG15599 - genes identified in a retinal degeneration screen to modify mutant YARS, also modified the mutant GARS phenotypes. Our study presents genetic evidence for common mutant-specific interactions between two CMT-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies.
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Biljana
authors.initials: B
authors.lastname: Ermanoska
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA; Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Motley
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Leitão-Gonçalves
authors.affiliation: Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Centralized Service Facility, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.affiliation: Department of Biological Sciences, Florida Atlantic University, Jupiter, FL 33458, USA.
authors.forename: LaTasha H
authors.initials: LH
authors.lastname: Lee
authors.affiliation: Applied Molecular Genomics Unit, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Rijk
authors.affiliation: Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Kristel
authors.initials: K
authors.lastname: Sleegers
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Tinne
authors.initials: T
authors.lastname: Ooms
authors.affiliation: Department of Biological Sciences, Florida Atlantic University, Jupiter, FL 33458, USA.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Godenschwege
authors.affiliation: Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium. Electronic address: albena.jordanova@molgen.vib-ua.be.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002607:Charcot-Marie-Tooth Disease / Q000150:complications* / Q000235:genetics* / Q000473:pathology; D003911:Dextrans; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D006032:Glycine-tRNA Ligase / Q000235:genetics*; D006801:Humans; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010523:Peripheral Nervous System Diseases / Q000209:etiology* / Q000235:genetics; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D012162:Retinal Degeneration / Q000175:diagnosis / Q000209:etiology / Q000235:genetics; D012235:Rhodamines; D014448:Tyrosine-tRNA Ligase / Q000235:genetics*; D014921:Wings, Animal / Q000473:pathology / Q000648:ultrastructure
chemical_list: D003911:Dextrans; D029721:Drosophila Proteins; C067661:Fluoro-Ruby; D012235:Rhodamines; D014448:Tyrosine-tRNA Ligase; D006032:Glycine-tRNA Ligase
keywords: Aminoacyl-tRNA synthetase; Charcot–Marie–Tooth disease; Drosophila