title: Targeting the ER-autophagy system in the trabecular meshwork to treat glaucoma.
abstract: A major drainage network involved in aqueous humor dynamics is the conventional outflow pathway, which is gated by the trabecular meshwork (TM). The TM acts as a molecular sieve, providing resistance to aqueous outflow, which is responsible for regulating intraocular pressure (IOP). If the TM is damaged, aqueous outflow is impaired, IOP increases and glaucoma can manifest. Mutations in the MYOC gene cause hereditary primary open-angle glaucoma (POAG) by promoting the abnormal amyloidosis of the myocilin protein in the endoplasmic reticulum (ER), leading to ER stress-induced TM cell death. Myocilin accumulation is observed in approximately 70-80% of all glaucoma cases suggesting that environmental or other genetic factors may also promote myocilin toxicity. For example, simply preventing myocilin glycosylation is sufficient to promote its abnormal accretion. These myocilin amyloids are unique as there are no other known pathogenic proteins that accumulate within the ER of TM cells and cause toxicity. Moreover, this pathogenic accumulation only kills TM cells, despite expression of this protein in other cell types, suggesting that another modifier exclusive to the TM participates in the proteotoxicity of myocilin. ER autophagy (reticulophagy) is one of the pathways essential for myocilin clearance that can be impacted dramatically by aging and other environmental factors such as nutrition. This review will discuss the link between myocilin and autophagy, evaluating the role of this degradation pathway in glaucoma as well as its potential as a therapeutic target.
authors: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA.
authors: Andrew R
authors: AR
authors: Stothert
authors: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA.
authors: Sarah N
authors: SN
authors: Fontaine
authors: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA.
authors: Jonathan J
authors: JJ
authors: Sabbagh
authors: Department of Molecular Medicine, Byrd Alzheimer's Research Institute, University of South Florida, Tampa, FL 33613, USA. Electronic address: cdickey@health.usf.edu.
authors: Chad A
authors: CA
authors: Dickey
mesh_terms: D000818:Animals; D001082:Aqueous Humor / Q000502:physiology; D001343:Autophagy / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005136:Eye Proteins / Q000378:metabolism; D005902:Glaucoma, Open-Angle / Q000188:drug therapy* / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007429:Intraocular Pressure / Q000502:physiology; D058990:Molecular Targeted Therapy; D014129:Trabecular Meshwork; D000099179:Myocilin
chemical_list: D003598:Cytoskeletal Proteins; D005136:Eye Proteins; D006023:Glycoproteins; D000099179:Myocilin
keywords: Autophagy; Glaucoma; Grp94; Myocilin; Trabecular meshwork