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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting millions globally.
• Mutations in tRNA synthetases are linked to CMT, causing defects in neuronal protein synthesis.
• Current treatments for CMT primarily manage symptoms, lacking disease-modifying options.

Purpose of the Study:

• To investigate the impact of CMT-linked tyrosyl tRNA synthetase (YARS-CMT) variants on neuronal protein synthesis and viability.
• To explore therapeutic strategies for rescuing protein synthesis and neuronal function in CMT.
• To examine the role of axon regeneration in restoring protein synthesis in CMT neurons.

Main Methods:

• Primary mouse sensory neurons expressing YARS-CMT variants were cultured.
• Protein synthesis levels and cell viability were assessed.
• Axon regeneration was induced by dissociating and replating neurons.
• The role of mTOR in protein synthesis rescue was investigated.

Main Results:

• YARS-CMT expression reduced protein synthesis in neurons before axon degeneration.
• Axonal regrowth occurred normally in replated YARS-CMT neurons, indicating successful regeneration.
• Regeneration via replating rescued protein synthesis in YARS-CMT neurons.
• mTOR inhibition suppressed the rescue of protein synthesis during regeneration.

Conclusions:

• Defective protein synthesis precedes axon degeneration in a cellular model of CMT.
• Stimulating neuronal regeneration can rescue protein synthesis and promote axon elongation despite CMT mutations.
• Targeting protein synthesis pathways, potentially involving mTOR, presents a promising therapeutic avenue for CMT and other neurological disorders.