Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterising Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor TrkB, underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice display early and persistent disturbances in axonal transport of neurotrophin-containing signalling endosomes in vivo. We discovered that BDNF-TrkB impairments correlate with transport disruption and overall CMT2D neuropathology, and that inhibition of this pathway at the nerve-muscle interface perturbs endosome transport in wildtype axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restores physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

Charcot-Marie-Tooth disease (CMT) is a form of genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which charge amino acids to partner tRNAs for protein synthesis, represent the largest protein family linked to CMT aetiology, suggestive of pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused byYARS1mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that DI-CMTC-causing TyrRSE196Kmis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for CMT type 2D (CMT2D)-causing mutant glycyl-tRNA synthetase. We then performed temporal neuromuscular assessments of recently generatedYarsE196Kmice modelling DI-CMT. Throughin vivoimaging of exposed sciatic nerves, we determined thatYarsE196Khomozygotes display a selective, age-dependent impairment in axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. Increasing BDNF in DI-CMTC mouse muscle, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a pathomechanism common to neuropathies caused by mutations inYARS1andGARS1, and highlights the potential of boosting BDNF in muscles as a therapeutic strategy to treat ARS-related CMTs.