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Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons

Lookup NU author(s): Dr Veronika Boczonadi, Dr Helen GriffinORCiD, Dr Andreas Roos, Marina Bartsakoulia, Dr Boglarka Bansagi, Giulia Ricci, Dr Francesco Bruni, Professor Hanns Lochmuller, Professor Rita HorvathORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2018. The nuclear-encoded glycyl-tRNA synthetase gene (GARS) is essential for protein translation in both cytoplasm and mitochondria. In contrast, different genes encode the mitochondrial and cytosolic forms of most other tRNA synthetases. Dominant GARS mutations were described in inherited neuropathies, while recessive mutations cause severe childhoodonset disorders affecting skeletal muscle and heart. The downstream events explaining tissue-specific phenotype-genotype relations remained unclear. We investigated the mitochondrial function of GARS in human cell lines and in the GarsC210R mouse model. Human-induced neuronal progenitor cells (iNPCs) carrying dominant and recessive GARS mutations showed alterations of mitochondrial proteins, which were more prominent in iNPCs with dominant, neuropathy-causing mutations. Although comparative proteomic analysis of iNPCs showed significant changes in mitochondrial respiratory chain complex subunits, assembly genes, Krebs cycle enzymes and transport proteins in both recessive and dominant mutations, proteins involved in fatty acid oxidation were only altered by recessive mutations causing mitochondrial cardiomyopathy. In contrast, significant alterations of the vesicle-associated membrane protein-associated protein B (VAPB) and its downstream pathways such as mitochondrial calciumuptake and autophagy were detected in dominant GARS mutations. The role of VAPB has been supported by similar results in the GarsC210R mice. Our data suggest that altered mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) may be important disease mechanisms leading to neuropathy in this condition.

Publication metadata

Author(s): Boczonadi V, Meyer K, Gonczarowska-Jorge H, Griffin H, Roos A, Bartsakoulia M, Bansagi B, Ricci G, Palinkas F, Zahedi RP, Bruni F, Kaspar B, Lochmuller H, Boycott KM, Muller JS, Horvath R

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2018

Volume: 27

Issue: 12

Pages: 2187-2204

Print publication date: 01/06/2018

Online publication date: 10/04/2018

Acceptance date: 27/03/2018

Date deposited: 22/10/2018

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddy127


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Funder referenceFunder name
MR/N025431/1Medical Research Council (MRC)