A Peptide-Based Strategy to Disrupt Oxidation-Induced Aggregation of γC-Crystallin Missense Mutant

Cataracts, a leading cause of blindness worldwide, are frequently associated with mutations in Crystallin genes. The G129C mutation in human γC-Crystallin (γC) leads to severe early onset congenital cataracts by introducing a solvent-exposed cysteine residue, though its pathogenic mechanism remains incompletely understood. This study demonstrates that the mutation renders the protein highly susceptible to oxidative stress, lowering the threshold for a deleterious phase transition that culminates in abnormal aggregation. Although the G129C mutant retains its native folded state, it undergoes rapid, concentration-dependent aggregation under mild oxidative stress, forming solid-like aggregates with distinctive structural properties. To counteract this pathology, we further identified an affinity peptide, Cand.2. Cand.2 selectively binds to G129C-induced aggregates and dissolves preformed aggregates in vitro. More importantly, it can alleviate oxidative stress-induced intracellular aggregation in cell models. This study elucidates the molecular pathway by which the G129C mutation leads to cataract formation and establishes a peptide-based targeted therapeutic strategy, offering a promising nonsurgical alternative to conventional broad-spectrum antioxidants for the treatment of hereditary cataracts.