Exploring the Molecular Landscape of HARS-Associated Charcot-Marie-Tooth Disease: Disease Mechanisms and Therapeutic Interventions

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy, with mutations in over 150 genes. The underlying pathology of CMT primarily involves either myelin sheath degradation or axonal damage, with no unifying molecular mechanism of disease. Notably, mutations in aminoacyl-tRNA synthetases have been linked to CMT2, with histidyl-tRNA synthetase (HARS) specifically implicated in CMT2W. These enzymes play a crucial role in charging tRNAs with their corresponding amino acids, facilitating peptide synthesis during mRNA translation. Here, I use a humanized HARS yeast model and protein biochemistry to investigate the molecular mechanisms associated with the disease-causing HARS variants V133F, Y330C, and Y138H, identifying mistranslation and impaired dimerization as disease-causing mechanisms in HARS-related CMT. I also demonstrate the feasibility of tRNAHis supplementation as a therapeutic with the rescue of mistranslation in V133F and Y330C and expand the potential use of histidine as a therapeutic option to the Y138H variant.