Citation Information: JCI Insight. 2023. https://doi.org/10.1172/jci.insight.157191.
Abstract
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 wild-type 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.
Authors
James N. Sleigh, David Villarroel-Campos, Sunaina Surana, Tahmina Wickenden, Yao Tong, Rebecca L. Simkin, Jose Norberto S. Vargas, Elena R. Rhymes, Andrew P. Tosolini, Steven J. West, Qian Zhang, Xiang-Lei Yang, Giampietro Schiavo
