Myocilin binding to a-b-crystallin sheds light on an old and blinding disease

Myocilin (MYOC) was discovered over 20 years ago and is the gene with mutations most commonly observed in glaucoma patients. Despite research efforts, the function of wild-type MYOC has remained elusive and how mutant MYOC is linked to glaucoma is ambiguous. Herein we present findings suggesting a mechanism by which mutant MYOC causes glaucoma. We generated multiple myocilin animal models, one of which was a rat CRISPR-engineered with a pathologic Myoc mutation. From our models, we discovered that a MYOC binding partner is a-b-crystallin (CRYAB). Mutant MYOC is misfolded and we believe it will aggregate with CRYAB to compromise protein clearance mechanisms. Our finding that MYOC binds CRYAB provides a mechanistic understanding how pathologic MYOC mutations cause glaucoma. We conclude that mutant MYOC-induced glaucoma is similar to other aging diseases which involve protein aggregation and therapeutic treatment should be directed at reducing these protein complexes and aggregates.