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Charcot-Marie-Tooth-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila

Ermanoska B1, Motley WW2, Leitão-Gonçalves R3, Asselbergh B4, Lee LH5, De Rijk P6, Sleegers K7, Ooms T1, Godenschwege TA5, Timmerman V8, Fischbeck KH9, Jordanova A10.

Neurobiol Dis. 2014 Aug;68:180-9.

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1Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium and

2Neurogenetics 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 and

3Molecular 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 and

4Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Centralized Service Facility, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium and

5Department of Biological Sciences, Florida Atlantic University, Jupiter, FL 33458, USA and

6Applied Molecular Genomics Unit, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium and

7Neurogenetics 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 and

8Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Peripheral Neuropathy Group, Department of Molecular Genetics, VIB, University of Antwerp, Antwerp 2610, Belgium and

9Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA and

10Molecular 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: [email protected]

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 Charcot-Marie-Tooth-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) inDrosophila, 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 Charcot-Marie-Tooth 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 Charcot-Marie-Tooth-associated aminoacyl-tRNA synthetases, lending support for a shared mechanism responsible for the synthetase-induced peripheral neuropathies.

Copyright © 2014 Elsevier Inc. All rights reserved.

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Charcot-Marie-Tooth-associated mutations glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern toxicity - global medical discovery