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 in 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 mTOR 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. Significance statement Peripheral neuropathies represent a challenging threat to human health, impacting quality of life for millions with limited treatment options beyond symptom management. Charcot-Marie-Tooth Disease (CMT) is the most common inherited peripheral neuropathy with some causative mutations identified in an enzyme family of tRNA synthetases. We use a cellular model of this disease to understand the mechanistic basis of CMT and identify novel ways to protect neuron function. We observe severe defects in protein synthesis in our model followed by axon degeneration. Most importantly, we rescue protein synthesis by stimulating a regenerative growth program in these neurons which promotes normal axon elongation despite CMT mutations. Restoring protein synthesis will have broad relevance to many neurological disorders and warrants additional investigation.
Koenig et al. (Tue,) studied this question.