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Replating Induces mTOR-Dependent Rescue of Protein Synthesis in Charcot-Marie-Tooth Diseased Neurons
Journal article   Open access   Peer reviewed

Replating Induces mTOR-Dependent Rescue of Protein Synthesis in Charcot-Marie-Tooth Diseased Neurons

Julianna Koenig, Alexys McGuire, Yara Homedan, Jessica Alberhasky and Daniel W Summers
eNeuro, Vol.13(3), pp.1-16
03/2026
DOI: 10.1523/ENEURO.0337-25.2026
PMCID: PMC13064590
PMID: 41876253
url
https://doi.org/10.1523/ENEURO.0337-25.2026View
Published (Version of record) Open Access

Abstract

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy characterized by sensory dysfunction and muscle weakness, manifesting in the most distal limbs first and progressing more proximal. Over a hundred genes are currently linked to CMT with enrichment for activities in myelination, axon transport, and protein synthesis. Mutations in tRNA synthetases cause dominantly inherited forms of CMT, and animal models with CMT-linked mutations in these enzymes display defects in neuronal protein synthesis. Rescuing protein synthesis in CMT-mutant neurons could offer exciting therapeutic options beyond symptom management. To address this need, we expressed CMT-linked variants of tyrosyl-tRNA synthetase (YARS-CMT) in primary mouse sensory neurons derived from both male and female embryos and evaluated impacts on protein synthesis and cell viability. YARS-CMT expression reduced protein synthesis in these neurons prior to the onset of caspase-dependent axon degeneration and cell death. To determine how YARS-CMT expression affects axon outgrowth, we dissociated and replated these neurons to stimulate axon regeneration. To our surprise, axonal regrowth occurred normally in replated YARS-CMT neurons. Moreover, replating YARS-CMT neurons rescued protein synthesis. Inhibiting mammalian target of rapamycin suppressed rescue of protein synthesis after replating, consistent with its significant role in protein synthesis during axon regeneration. These discoveries identify new avenues for augmenting protein synthesis in diseased neurons and restoring protein synthesis in CMT or other neurological disorders.
 Animals Axons - metabolism Cells, Cultured Charcot-Marie-Tooth Disease - genetics Charcot-Marie-Tooth Disease - metabolism Charcot-Marie-Tooth Disease - pathology Female Ganglia, Spinal Male Mice Nerve Regeneration - physiology Protein Biosynthesis - physiology Sensory Receptor Cells - metabolism TOR Serine-Threonine Kinases - metabolism Tyrosine-tRNA Ligase - genetics Tyrosine-tRNA Ligase - metabolism

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