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

Lynch, Jeffrey and Li, Bing and Katoli, Parvaneh and Xiang, Chuanxi and Leehy, Barrett and Rangaswamy, Nalini and Saenz-Vash, Veronica and Wang, Yingqi and Lei, Hong and Nicholson, Thomas and Meredith, Erik and Chen, Amy and Prasanna, Ganesh and Rice, Dennis (2018) Myocilin binding to a-b-crystallin sheds light on an old and blinding disease. Journal of Biological Chemistry, 293 (52). pp. 20137-20156.

Abstract

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.

Item Type: Article
Date Deposited: 16 Jan 2019 00:45
Last Modified: 16 Jan 2019 00:45
URI: https://oak.novartis.com/id/eprint/34428

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