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

Abstract

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.

BDNF controls phosphorylation and transcriptional networks governing cytoskeleton organization and axonal regeneration

“…It is tempting to speculate that locally activated ERK1/2 is able to hitchhike on SEs back to soma to switch on pro-survival programs. Our previous work showed that local muscle administration or viral overexpression of BDNF in muscles corrects axonal transport defects of SEs and pathological symptoms in peripheral neuropathy mouse models 73,92 .…”