Molecular Details of Protein Misfolding in Myocilin-Associated Glaucoma

Inherited missense mutations in the myocilin olfactomedin domain are causative for early-onset glaucoma, via a toxic gain of function. We have elaborated atomic-level details misfolding relevant to glaucoma pathogenesis. Pathogenic olfactomedin-resident mutations, which account 90% all documented disease variants, destabilized and undergo templated amyloid-like aggregation under mild physiological conditions. In cell, mutant recruits endoplasmic reticulum-resident chaperone Grp94 into its aggregate, precluding proteosomal degradation. Resultant cytotoxicity ultimately compromises function trabecular meshwork, key ocular tissue where is expressed at high level diseased most forms glaucoma. Taken together, our work offers new disease-modifying therapeutic strategies treat myocilin-associated