Mutations in glycyl-tRNA synthetase impair mitochondrial metabolism in neurons.

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

doi:10.1093/hmg/ddy127

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.

Highlights

All genes are copied into short-lived RNA molecules, which are translated to proteins, forming the building box of the cells in the body
Genetic reduction of neuropilin 1 (Nrp1) in mice worsens neuropathy, whereas enhanced expression of vascular endothelial growth factor (VEGF) improves motor function. It seems to be an important pathomechanism of the secreted GARS outside the neurons it does not explain all abnormalities observed in GARS mutations
In this study we identified that reduction or loss of GARS result in decreased translation of mtDNA and nuclear encoded subunits confirming that GARS is important for obtaining mitochondrial

Summary

Introduction

All genes are copied into short-lived RNA molecules, which are translated to proteins, forming the building box of the cells in the body. The majority of genes which regulate protein translation in these cellular compartments are distinct, but two genes encoding aminoacyl-tRNA synthetases of glycine (GARS) and lysine (KARS) are common, in both mitochondria and the cytosol [2]. Homozygous for c.2065C>T, p.(Arg689Trp), had severe neonatal cardiomyopathy and cytochrome c oxidase deficiency and died at 10 days of age [3] Another child with compound heterozygous c.1904C>T, p.(Ser635Leu) and c.1787G>A, p.(Arg596Gln) presented with exercise-induced myalgia, non-compaction cardiomyopathy, periventricular lesions and increased lactate [4]. Recessive mutations within the catalytic domain were reported causing multisystem disease with growth retardation, delayed motor milestones, dysmorphic signs and complex neurological presentation of microcephaly, thinning of the corpus callosum, white matter lesions, cerebellar vermis and brainstem atrophy, but without peripheral neuropathy [5]. A mild neuropathy was observed on electrophysiological testing in the heterozygous father of the second child [4]

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