ArticleHuman molecular genetics2015
Dominant, toxic gain-of-function mutations in gars lead to non-cell autonomous neuropathology.
Article in Human molecular genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 54 citations in OpenAlex.
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- Cost-effective non-additive GWAS across 2329 diseases in 500,349 individuals.Nature communications · 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
- Article
- Dominant aminoacyl-tRNA synthetase disorders: lessons learned fromFrontiers in neuroscience · 2023Review
- Motor defects in a Drosophila model for spinal muscular atrophy result from SMN depletion during early neurogenesis.PLoS genetics · 2022Article
- Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes.Human mutation · 2022Article
- Therapeutic Potential of CKD-504, a Novel Selective Histone Deacetylase 6 Inhibitor, in a Zebrafish Model of Neuromuscular Junction Disorders.Molecules and cells · 2022Article
- HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D).Advanced biology · 2022Article
- Review
- Modelling and Refining Neuronal Circuits with Guidance Cues: Involvement of Semaphorins.International journal of molecular sciences · 2021Review
- SIRT2-knockdown rescues GARS-induced Charcot-Marie-Tooth neuropathy.Aging cell · 2021Article
- Aminoacyl-tRNA synthetases in Charcot-Marie-Tooth disease: A gain or a loss?Journal of neurochemistry · 2021Review
- AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements inBrain communications · 2021Article
- An Integrated Approach to Studying Rare Neuromuscular Diseases Using Animal and Human Cell-Based Models.Frontiers in cell and developmental biology · 2021Review
- Developmental demands contribute to early neuromuscular degeneration in CMT2D mice.Cell death & disease · 2020Article
- Altered Sensory Neuron Development in CMT2D Mice Is Site-Specific and Linked to Increased GlyRS Levels.Frontiers in cellular neuroscience · 2020Article
- CMT disease severity correlates with mutation-induced open conformation of histidyl-tRNA synthetase, not aminoacylation loss, in patient cells.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Neurodegenerative Charcot-Marie-Tooth disease as a case study to decipher novel functions of aminoacyl-tRNA synthetases.The Journal of biological chemistry · 2019Review
Corrections and comments
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Authors and funding
7 authors at 5 institutions in 2 countries.
Funding
Abstract
Charcot-Marie-Tooth (CMT) neuropathies are collectively the most common hereditary neurological condition and a major health burden for society. Dominant mutations in the gene GARS, encoding the ubiquitous enzyme, glycyl-tRNA synthetase (GlyRS), cause peripheral nerve degeneration and lead to CMT disease type 2D. This genetic disorder exemplifies a recurring motif in neurodegeneration, whereby mutations in essential, widely expressed genes have selective deleterious consequences for the nervous system. Here, using novel Drosophila models, we show a potential solution to this phenomenon. Ubiquitous expression of mutant GlyRS leads to motor deficits, progressive neuromuscular junction (NMJ) denervation and pre-synaptic build-up of mutant GlyRS. Intriguingly, neuronal toxicity is, at least in part, non-cell autonomous, as expression of mutant GlyRS in mesoderm or muscle alone results in similar pathology. This mutant GlyRS toxic gain-of-function, which is WHEP domain-dependent, coincides with abnormal NMJ assembly, leading to synaptic degeneration, and, ultimately, reduced viability. Our findings suggest that mutant GlyRS gains access to ectopic sub-compartments of the motor neuron, providing a possible explanation for the selective neuropathology caused by mutations in a widely expressed gene.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.