Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy

Abstract

Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot–Marie–Tooth (CMT) peripheral neuropathy.

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.

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—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.

Thus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.

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BibTeX RIS

BibTeX

@article{mallik2026tyrosyltrna,
  title = {{Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy}},
  author = {Moushami Mallik and Abigail L D Tadenev and Natalia Mora and Vanessa Lewandowski and Daniel Köster and María Landínez-Macías and Robin Thompson and María P Menafra and Noah K Taylor and Pascal van Lith and Nick van Bakel and Marica Catinozzi and Scott Q Harper and Zoya Ignatova and Robert W Burgess and Erik Storkebaum},
  journal = {Brain},
  year = {2026},
  month = aug,
  doi = {10.1093/brain/awag204},
  url = {https://doi.org/10.1093/brain/awag204},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - Tyrosyl-tRNA sequestration triggers tyrosyl-tRNA synthetase-associated peripheral neuropathy
AU  - Moushami Mallik
AU  - Abigail L D Tadenev
AU  - Natalia Mora
AU  - Vanessa Lewandowski
AU  - Daniel Köster
AU  - María Landínez-Macías
AU  - Robin Thompson
AU  - María P Menafra
AU  - Noah K Taylor
AU  - Pascal van Lith
AU  - Nick van Bakel
AU  - Marica Catinozzi
AU  - Scott Q Harper
AU  - Zoya Ignatova
AU  - Robert W Burgess
AU  - Erik Storkebaum
PY  - 2026
DA  - 2026/08/12
JO  - Brain
DO  - 10.1093/brain/awag204
UR  - https://doi.org/10.1093/brain/awag204
AB  - Mono-allelic mutations in seven cytosolic aminoacyl-tRNA synthetase genes cause Charcot–Marie–Tooth (CMT) peripheral neuropathy.  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.  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—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.  Thus, elevating tRNATyr levels constitutes a novel therapeutic approach for CMT-YARS1.
SN  - 0006-8950
SN  - 1460-2156
ER  -

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