Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons

Boczonadi, Veronika; Meyer, Kathrin; Gonczarowska-Jorge, Humberto; Griffin, Helen; Roos, Andreas; Bartsakoulia, Marina; Bansagi, Boglarka; Ricci, Giulia; Palinkas, Fanni; Zahedi, René P.; Bruni, Francesco; Kaspar, Brian; Lochmüller, Hanns; Boycott, Kym M.; Müller, Juliane; Horvath, Rita

Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons

Mostra el registre complet Registre parcial de l'ítem

dc.contributor.author Boczonadi, Veronika
dc.contributor.author Meyer, Kathrin
dc.contributor.author Gonczarowska-Jorge, Humberto
dc.contributor.author Griffin, Helen
dc.contributor.author Roos, Andreas
dc.contributor.author Bartsakoulia, Marina
dc.contributor.author Bansagi, Boglarka
dc.contributor.author Ricci, Giulia
dc.contributor.author Palinkas, Fanni
dc.contributor.author Zahedi, René P.
dc.contributor.author Bruni, Francesco
dc.contributor.author Kaspar, Brian
dc.contributor.author Lochmüller, Hanns
dc.contributor.author Boycott, Kym M.
dc.contributor.author Müller, Juliane
dc.contributor.author Horvath, Rita
dc.date.accessioned 2019-11-20T08:48:42Z
dc.date.available 2019-11-20T08:48:42Z
dc.date.issued 2018
dc.description.abstract 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 childhood-onset 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 calcium uptake 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.
dc.description.sponsorship R.H. is a Wellcome Investigator (109915/Z/15/Z) supported by the Wellcome Centre for Mitochondrial Research (203105/Z/16/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548) and the Mitochondrial European Educational Training (MEET), ITN MARIE CURIE PEOPLE, (317433). H.L. receives funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement No. 305444 (RD-Connect), 305121 (Neuromics), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z) and the Newton Fund (UK/Turkey, MR/N027302/1). H.J.G., A.R. and R.P.Z. acknowledge the financial support by the Ministeriumfür Innovation, Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the SenatsverwaltungfürWirtschaft, Technologie und Forschung des Landes Berlin, and the BundesministeriumfürBildung und Forschung. H.G.J. further thanks the CAPES Foundation for financial support.
dc.format.mimetype application/pdf
dc.identifier.citation 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, Lochmüller H, Boycott KM11, Müller JS1, Horvath R. Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons. Hum Mol Genet. 2018; 27(12):2187-2204. DOI 10.1093/hmg/ddy127
dc.identifier.doi http://dx.doi.org/10.1093/hmg/ddy127
dc.identifier.issn 0964-6906
dc.identifier.uri http://hdl.handle.net/10230/42907
dc.language.iso cat
dc.publisher Oxford University Press
dc.relation.ispartof Hum Mol Genet. 2018; 27(12):2187-2204
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309548
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305444
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/305121
dc.rights © The Author(s) 2018. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.subject.keyword Mutation
dc.subject.keyword Mitochondria
dc.subject.keyword Glycine-trna ligase
dc.subject.keyword Mice
dc.title Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Center for Genomic Regulation (CRG))
Documents OpenAIRE (Open Access Infrastructure for Research in Europe)