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 characterizing
Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different
proteins, including
neurotrophin receptor tropomyosin receptor
kinase receptor B (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 displayed early and persistent disturbances in axonal transport of
neurotrophin-containing signaling endosomes in vivo. We discovered that
brain-derived neurotrophic factor (
BDNF)/TrkB impairments correlated with transport disruption and overall
CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Accordingly, supplementation of muscles with
BDNF, but not other
neurotrophins, completely restored 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.