{
  "abstract": "Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot–Marie–Tooth (CMT) peripheral neuropathy.\n\nHere, we report that tyrosyl-tRNA (tRNATyr) sequestration by CMT-mutant tyrosyl-tRNA synthetase (TyrRS) is the molecular root cause of CMT-YARS1. tRNATyr sequestration depletes the cellular free tRNATyr pool, leading to insufficient tyrosyl-tRNATyr production and ribosome stalling at tyrosine codons.\n\nIn three Drosophila CMT-YARS1 models, transgenic overexpression of tRNATyr rescued peripheral neuropathy phenotypes and defective mRNA translation. We provide biochemical evidence for tRNATyr sequestration by the three CMT-TyrRS variants expressed in the Drosophila models and ribosome profiling revealed selective ribosome pausing at the two tyrosine codons. In the Yars1E196K mouse model, adeno-associated virus serotype 9 (AAV9)-mediated overexpression of tRNATyr—but not wild-type TyrRS protein—fully rescued motor performance deficits, reduced nerve conduction velocity and reduced motor axon calibre. Furthermore, AAV9-tRNATyr gene therapy prevented activation of the integrated stress response in spinal motor neurons, indicating resolution of ribosome stalling.\n\nThus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "Moushami Mallik"
    },
    {
      "name": "Abigail L D Tadenev"
    },
    {
      "name": "Natalia Mora"
    },
    {
      "name": "Vanessa Lewandowski"
    },
    {
      "name": "Daniel Köster"
    },
    {
      "name": "María Landínez-Macías"
    },
    {
      "name": "Robin Thompson"
    },
    {
      "name": "María P Menafra"
    },
    {
      "name": "Noah K Taylor"
    },
    {
      "name": "Pascal van Lith"
    },
    {
      "name": "Nick van Bakel"
    },
    {
      "name": "Marica Catinozzi"
    },
    {
      "name": "Scott Q Harper"
    },
    {
      "name": "Zoya Ignatova",
      "orcid": "0000-0002-9478-8825"
    },
    {
      "name": "Robert W Burgess",
      "orcid": "0000-0002-9229-3407"
    },
    {
      "name": "Erik Storkebaum",
      "orcid": "0000-0002-9519-5642"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ab3e1ga1w9e9r.bib",
  "cited_by": 2,
  "doi": "10.1093/brain/awag204",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13730582/",
  "id": "ab3e1ga1w9e9r",
  "issns": [
    "0006-8950",
    "1460-2156"
  ],
  "landing_url": "https://doi.org/10.1093/brain/awag204",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/MED00310"
    ],
    [
      "heading",
      "AcademicSubjects/SCI01870"
    ],
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2804|Hereditary Neurological Disorders"
    ]
  ],
  "openalex": "W7211900003",
  "pdf_url": null,
  "pmcid": "PMC13730582",
  "pmid": "42703926",
  "published": "2026-08-12",
  "publisher": "Oxford University Press",
  "ris": "https://research.draconitic.com/paper/ab3e1ga1w9e9r.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:23:06Z",
      "native_id": "PMC13730582",
      "source": "pmc",
      "url": "https://doi.org/10.1093/brain/awag204"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Hereditary Neurological Disorders",
      "subfield": "neuroscience"
    }
  ],
  "title": "Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy",
  "title_text": "Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:23:06Z",
  "url": "https://research.draconitic.com/paper/ab3e1ga1w9e9r",
  "venue": "Brain",
  "versions": []
}