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A. Maeda, T. Maeda, M. Golczak, K. Palczewski; Anomalous Reactions of the Visual Cycle Initiate Retinal Changes Found in Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):777.
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We examined how all-trans-retinal clearance delay affects on the retina, because 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 the RPE atrophy leading to an onset of retinopathy.
We developed 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.
Rdh8-/-Abca4-/- mice developed severe RPE/photoreceptor dystrophy at an early age. This phenotype mimicked typical features of human age-related macular degeneration (AMD), including 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 slow flow of all-trans-retinal through the visual cycle.
These findings provide direct evidence that aberrant production of toxic condensation byproducts by the visual cycle in mice can lead to rapid, progressive retinal degeneration.
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