TFG p.G269V Mutation Disrupts Motor Neuron Function in iPSC-Derived Models via Wnt Signaling Dysregulation.

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Charcot-Marie-Tooth disease (CMT) is an inherited neuropathy linked to TRK-fused gene (TFG) mutations, but pathogenic mechanisms are unclear.
• Previous studies showed TFG p.G269V mutation impairs neurite outgrowth and induces neuronal apoptosis, suggesting a neurodevelopmental role.

Purpose of the Study:

• To investigate the effects of the TFG p.G269V mutation on human motor neurons (MNs) using induced pluripotent stem cells (iPSCs).
• To explore potential therapeutic strategies for TFG-associated neuropathy.

Main Methods:

• Generated patient-derived iPSCs and CRISPR/Cas9-corrected homologous lines.
• Differentiated iPSCs into motor neurons for comparative analysis.
• Assessed MN morphology, protein aggregation, electrophysiology, and transcriptomics (Wnt signaling).

Main Results:

• Patient-derived MNs showed axonal shortening, TFG-associated insoluble material, and functional deficits (reduced action potentials, elevated rheobase).
• Transcriptomic analysis revealed Wnt signaling dysregulation, which worsened neuronal excitability when inhibited.
• Genetic correction using CRISPR/Cas9 reversed the observed MN defects.

Conclusions:

• The TFG p.G269V mutation autonomously disrupts human motor neuron morphology and function.
• Genetic correction can reverse these defects, offering a potential therapeutic avenue.
• Dysregulated Wnt signaling may play a significant role in the pathophysiology of TFG-associated neuropathy.