Document Type
Article
Publication Date
6-1-2024
Original Citation
Rhymes E,
Simkin R,
Qu J,
Villarroel-Campos D,
Surana S,
Tong Y,
Shapiro R,
Burgess RW,
Yang X,
Schiavo G,
Sleigh J.
Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy. Neurobiol Dis. 2024;195:106501
Keywords
JGM, Animals, Charcot-Marie-Tooth Disease, Brain-Derived Neurotrophic Factor, Mice, Axonal Transport, Disease Models, Animal, Tyrosine-tRNA Ligase, Humans, Mice, Transgenic, Muscle, Skeletal, Receptor, trkB, Mutation
JAX Source
Neurobiol Dis. 2024;195:106501
ISSN
1095-953X
PMID
38583640
DOI
https://doi.org/10.1016/j.nbd.2024.106501
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 patho- mechanistic 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.
Comments
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).