Affiliation:
1. Beijing Institute of Ophthalmology
2. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University
3. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Ophthalmology & Visual Sciences Key Laboratory
Abstract
Abstract
Glaucoma is a highly heritable disease and myocilin was the first identified causal gene and most common pathogenic gene in glaucoma. Serine to proline mutation at position 341 of myocilin (MYOCS341P) is associated with severe glaucoma phenotypes in a five generation of primary open angle glaucoma family. But the underlying mechanisms is under explored. Here, we established MYOCS341P transgenic mouse model and characterized the glaucoma phenotypes. Further, we systematically explored the differences in function between wild-type and MYOCS341P by immunoprecipitation followed by mass spectrometry and RNA-seq analyses. We found that MYOCS341P transgenic mouse exhibit glaucoma phenotypes, characterized by reduced aqueous humor outflow, elevated intraocular pressure, decreased trabecular meshwork (TM) cells number, narrowed Schlemm’s canal, retinal ganglion cell loss, and visual impairment. Mechanistically, secretion incompetent MYOCS341P accumulated in the endoplasmic reticulum (ER), induced ER stress, and causes deregulation of autophagy, thereby promoting TM cell death. We describe an effective transgenic model for mechanistic studies and screening of therapeutic targets. And our data generated from high-throughput analyses help to elucidate the mechanism underlying mutant MYOC-related glaucoma.
Publisher
Research Square Platform LLC