Retinopathy in mice induced by disrupted all-trans-retinal clearance

被引:239
|
作者
Maeda, Akiko [1 ]
Maeda, Tadao [1 ,2 ]
Golczak, Marcin [1 ]
Palczewski, Krzysztof [1 ]
机构
[1] Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Sch Med, Dept Ophthalmol, Cleveland, OH 44106 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1074/jbc.M804505200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:26684 / 26693
页数:10
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