{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T06:13:12Z","timestamp":1791958392757,"version":"4.3.4"},"reference-count":36,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"ERC","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Radala Foundation"},{"DOI":"10.13039\/501100014076","name":"Stichting ALS Nederland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100014076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004923","name":"AFM-Telethon","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006510","name":"ARSLA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004243","name":"Prinses Beatrix Spierfonds","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004243","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EU Joint Programme\u2014"},{"DOI":"10.13039\/100013278","name":"EU Joint Programme\u2014Neurodegenerative Disease Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100013278","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016036","name":"Health\u223cHolland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Biotech Booster"},{"name":"DI-NIN Fund"},{"name":"NWO Take-off WO Phase I"},{"name":"Donders Center for Neuroscience"},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot\u2013Marie\u2013Tooth (CMT) peripheral neuropathy.<\/jats:p>\n                  <jats:p>Here, 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.<\/jats:p>\n                  <jats:p>In 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\u2014but not wild-type TyrRS protein\u2014fully 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.<\/jats:p>\n                  <jats:p>Thus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.<\/jats:p>","DOI":"10.1093\/brain\/awag204","type":"journal-article","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T11:43:37Z","timestamp":1780746217000},"source":"Crossref","is-referenced-by-count":1,"title":["Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy"],"prefix":"10.1093","author":[{"given":"Moushami","family":"Mallik","sequence":"first","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail L D","family":"Tadenev","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME 04609 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Mora","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Lewandowski","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg , Hamburg 20146 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"K\u00f6ster","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg , Hamburg 20146 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Land\u00ednez-Mac\u00edas","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Thompson","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg , Hamburg 20146 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda P","family":"Menafra","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah K","family":"Taylor","sequence":"additional","affiliation":[{"name":"Jerry R. Mendell Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital , Columbus, OH 43202 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pascal","family":"van Lith","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"van Bakel","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marica","family":"Catinozzi","sequence":"additional","affiliation":[{"name":"Molecular Neurobiology Laboratory, Donders Institute for Brain, Cognition and Behaviour and Faculty of Science, Radboud University , Nijmegen 6525 AJ ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott Q","family":"Harper","sequence":"additional","affiliation":[{"name":"Jerry R. Mendell Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children\u2019s Hospital , Columbus, OH 43202 ,","place":["USA"]},{"name":"Department of Pediatrics, The Ohio State University College of Medicine , Columbus, OH 43201 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-8825","authenticated-orcid":false,"given":"Zoya","family":"Ignatova","sequence":"additional","affiliation":[{"name":"Biochemistry and Molecular Biology, Department of Chemistry, University of Hamburg , Hamburg 20146 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME 04609 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