title: Di-retinoid-pyridinium-ethanolamine (A2E) Accumulation and the Maintenance of the Visual Cycle Are Independent of Atg7-mediated Autophagy in the Retinal Pigmented Epithelium.
abstract: Autophagy is an evolutionarily conserved catabolic mechanism that relieves cellular stress by removing/recycling damaged organelles and debris through the action of lysosomes. Compromised autophagy has been implicated in many neurodegenerative diseases, including retinal degeneration. Here we examined retinal phenotypes resulting from RPE-specific deletion of the autophagy regulatory gene Atg7 by generating Atg7(flox/flox);VMD2-rtTA-cre+ mice to determine whether autophagy is essential for RPE functions including retinoid recycling. Atg7-deficient RPE displayed abnormal morphology with increased RPE thickness, cellular debris and vacuole formation indicating that autophagy is important in maintaining RPE homeostasis. In contrast, 11-cis-retinal content, ERGs and retinal histology were normal in mice with Atg7-deficient RPE in both fasted and fed states. Because A2E accumulation in the RPE is associated with pathogenesis of both Stargardt disease and age-related macular degeneration (AMD) in humans, deletion of Abca4 was introduced into Atg7(flox/flox);VMD2-rtTA-cre+ mice to investigate the role of autophagy during A2E accumulation. Comparable A2E concentrations were detected in the eyes of 6-month-old mice with and without Atg7 from both Abca4(-/-) and Abca4(+/+) backgrounds. To identify other autophagy-related molecules involved in A2E accumulation, we performed gene expression array analysis on A2E-treated human RPE cells and found up-regulation of four autophagy related genes; DRAM1, NPC1, CASP3, and EIF2AK3/PERK. These observations indicate that Atg7-mediated autophagy is dispensable for retinoid recycling and A2E deposition; however, autophagy plays a role in coping with stress caused by A2E accumulation.
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Perusek
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences.
authors.forename: Bhubanananda
authors.initials: B
authors.lastname: Sahu
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences.
authors.forename: Tanu
authors.initials: T
authors.lastname: Parmar
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maeno
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Arai
authors.affiliation: Departments of Medicine Endocrinology, Cell Biology, and Ophthalmology and Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104.
authors.forename: Yun-Zheng
authors.initials: YZ
authors.lastname: Le
authors.affiliation: Medicine, Case Western Reserve University, Cleveland, Ohio 44106 and.
authors.forename: Carlos S
authors.initials: CS
authors.lastname: Subauste
authors.affiliation: Pharmacology and Cleveland Center for Membrane and Structural Biology, and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Pharmacology and Cleveland Center for Membrane and Structural Biology, and.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
authors.affiliation: From the Departments of Ophthalmology and Visual Sciences, Pharmacology and Cleveland Center for Membrane and Structural Biology, and aam19@case.edu.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008268:Macular Degeneration / Q000151:congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D012176:Retinoids / Q000235:genetics / Q000378:metabolism*; D000080362:Stargardt Disease; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism*; D014785:Vision, Ocular
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); C502661:Atg7 protein, mouse; D005136:Eye Proteins; D008869:Microtubule-Associated Proteins; D012176:Retinoids; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes
keywords: A2E; ABCA4; Stargardt disease; aging; autophagy; autophagy-related protein 7 (ATG7); retina; retinal degeneration