title: Retinopathy in mice induced by disrupted all-trans-retinal clearance.
abstract: The visual (retinoid) cycle is a fundamental metabolic process in vertebrate retina responsible for production of 11-cis-retinal, the chromophore of rhodopsin and cone pigments. 11-cis-Retinal is bound to opsins, forming visual pigments, and when the resulting visual chromophore 11-cis-retinylidene is photoisomerized to all-trans-retinylidene, all-trans-retinal is released from these receptors. Toxic byproducts of the visual cycle formed from all-trans-retinal often are associated with lipofuscin deposits in the retinal pigmented epithelium (RPE), but it is not clear whether aberrant reactions of the visual cycle participate in RPE atrophy, leading to a rapid onset of retinopathy. Here we report that mice lacking both the ATP-binding cassette transporter 4 (Abca4) and enzyme retinol dehydrogenase 8 (Rdh8), proteins critical for all-trans-retinal clearance from photoreceptors, developed severe RPE/photoreceptor dystrophy at an early age. This phenotype includes lipofuscin, drusen, and basal laminar deposits, Bruch's membrane thickening, and choroidal neovascularization. Importantly, the severity of visual dysfunction and retinopathy was exacerbated by light but attenuated by treatment with retinylamine, a visual cycle inhibitor that slows the flow of all-trans-retinal through the visual cycle. These findings provide direct evidence that aberrant production of toxic condensation byproducts of the visual cycle in mice can lead to rapid, progressive retinal degeneration.
authors.affiliation: Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Maeda
authors.forename: Tadao
authors.initials: T
authors.lastname: Maeda
authors.forename: Marcin
authors.initials: M
authors.lastname: Golczak
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Palczewski
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology; D008062:Lipofuscin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010857:Pigment Epithelium of Eye / Q000378:metabolism* / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D015593:Retinal Drusen / Q000235:genetics / Q000378:metabolism; D012172:Retinaldehyde / Q000235:genetics / Q000378:metabolism*; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism*; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism*; D014785:Vision, Ocular / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D000429:Alcohol Oxidoreductases; D008062:Lipofuscin; D012172:Retinaldehyde; D012243:Rhodopsin; C512841:Abca4 protein, mouse; C525880:HSD17B6 protein, mouse