title: Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma.
abstract: Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients.
authors.affiliation: Howard Hughes Medical Institute, Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Gulab S
authors.initials: GS
authors.lastname: Zode
authors.forename: Markus H
authors.initials: MH
authors.lastname: Kuehn
authors.forename: Darryl Y
authors.initials: DY
authors.lastname: Nishimura
authors.forename: Charles C
authors.initials: CC
authors.lastname: Searby
authors.forename: Kabhilan
authors.initials: K
authors.lastname: Mohan
authors.forename: Sinisa D
authors.initials: SD
authors.lastname: Grozdanic
authors.forename: Kevin
authors.initials: K
authors.lastname: Bugge
authors.forename: Michael G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Stone
authors.forename: Val C
authors.initials: VC
authors.lastname: Sheffield
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005136:Eye Proteins / Q000235:genetics; D005902:Glaucoma, Open-Angle / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D006023:Glycoproteins / Q000235:genetics; D006801:Humans; D007429:Intraocular Pressure; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010641:Phenotype; D010654:Phenylbutyrates / Q000494:pharmacology* / Q000627:therapeutic use*; D013312:Stress, Physiological; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D019076:Transgenes; D056811:Unfolded Protein Response; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D010654:Phenylbutyrates; D000099179:Myocilin