Missense mutations in myocilin are causative for the early-onset, hereditary form of open angle glaucoma. Using biophysical and structural methods, we have assembled a molecular picture of myocilin, including its wild-type supramolecular arrangement as defined by its coiled coil and olfactomedin domains, as well as its pathogenic misfolding. Annotated glaucoma-causing variants within each structural domain exhibit different protein defects. The olfactomedin domain, which harbors 90% of annotated variants, is exquisitely sensitive to mutation. Most olfactomedin-resident mutations are destabilizing and promote templated amyloid-like aggregation within the endoplasmic reticulum (ER). This misfolding includes an aberrant interaction with the ER-resident chaperone Grp94, resulting in cytotoxicity that compromises the function of the trabecular meshwork, a key ocular tissue diseased in most forms of glaucoma. Taken together, our work has elaborated atomic-level details of myocilin misfolding relevant to glaucoma pathogenesis and offers a new, disease-modifying therapeutic strategy to treat myocilin-associated glaucoma.

Molecular details of protein misfolding in myocilin-associated glaucoma

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.