Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy

Neurobiol Dis. 2024 Jun 1:195:106501. doi: 10.1016/j.nbd.2024.106501. Epub 2024 Apr 6.

Abstract

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations 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 human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Keywords: Aminoacyl-tRNA synthetase (ARS); Charcot-Marie-tooth disease (CMT); Intravital imaging; Motor neuron; Neuromuscular junction (NMJ); Neurotrophic factors; Neurotrophins; Peripheral neuropathy; Trk receptors; YARS1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Axonal Transport*
  • Brain-Derived Neurotrophic Factor* / genetics
  • Brain-Derived Neurotrophic Factor* / metabolism
  • Charcot-Marie-Tooth Disease* / genetics
  • Charcot-Marie-Tooth Disease* / metabolism
  • Disease Models, Animal*
  • Humans
  • Mice
  • Mice, Transgenic
  • Muscle, Skeletal / metabolism
  • Mutation
  • Receptor, trkB / genetics
  • Receptor, trkB / metabolism
  • Tyrosine-tRNA Ligase / genetics
  • Tyrosine-tRNA Ligase / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Tyrosine-tRNA Ligase
  • Bdnf protein, mouse
  • Receptor, trkB