ArticleNeurobiology of disease2014
CMT-associated mutations in glycyl- and tyrosyl-tRNA synthetases exhibit similar pattern of toxicity and share common genetic modifiers in Drosophila.
Article in Neurobiology of disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 37 citations in OpenAlex.
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- Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.Brain : a journal of neurology · 2026Article
- Glycyl-tRNA sequestration is a unifying mechanism underlying GARS1-associated peripheral neuropathy.Nucleic acids research · 2025Article
- Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.Neurobiology of disease · 2024Article
- Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.bioRxiv : the preprint server for biology · 2024Article
- An Adapted GeneSwitch Toolkit for Comparable Cellular and Animal Models: A Proof of Concept in Modeling Charcot-Marie-Tooth Neuropathy.International journal of molecular sciences · 2023Article
- Low-Dose Trans-Resveratrol Ameliorates Diabetes-Induced Retinal Ganglion Cell Degeneration via TyrRS/c-Jun Pathway.Investigative ophthalmology & visual science · 2023Article
- Article
- Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling.Nature communications · 2023Article
- Dominant aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Review
- Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss?Journal of neurochemistry · 2021Review
- Recent Advances inInternational journal of molecular sciences · 2020Review
- Overlapping spectrums: The clinicogenetic commonalities between Charcot-Marie-Tooth and other neurodegenerative diseases.Brain research · 2020Review
- Anterograde Axonal Transport in Neuronal Homeostasis and Disease.Frontiers in molecular neuroscience · 2020Review
- Transcriptional dysregulation by a nucleus-localized aminoacyl-tRNA synthetase associated with Charcot-Marie-Tooth neuropathy.Nature communications · 2019Article
- Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases.The Journal of biological chemistry · 2019Review
- HDAC6 is a therapeutic target in mutant GARS-induced Charcot-Marie-Tooth disease.Brain : a journal of neurology · 2018Article
- The role of tRNA synthetases in neurological and neuromuscular disorders.FEBS letters · 2018Review
- Plexin-Semaphorin Signaling Modifies Neuromuscular Defects in aFrontiers in molecular neuroscience · 2018Article
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Authors and funding
12 authors at 4 institutions in 2 countries.
Funding
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.
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