Retinopathy in mice induced by disrupted all-trans-retinal clearance
Retinopathy in mice induced by disrupted all-trans-retinal clearance
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DOI：
10.1074/jbc.m804505200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Palczewski, Krzysztof
中科院分区：
文献类型：
--
作者：
Maeda, Akiko;Maeda, Tadao;Palczewski, Krzysztof
视觉(类视网膜)循环是脊椎动物视网膜的一个基本代谢过程，负责产生11顺式视网膜，视紫质和视锥色素的生色团。11-顺式视黄醇与视黄素结合，形成视觉色素，当产生的视觉发色团11-顺式视黄醇被光异构化为全反式视黄醇时，全反式视黄醇从这些受体中释放出来。视网膜色素上皮(RPE)中的脂褐素沉积通常与全跨视网膜形成的视觉周期的有毒副产物有关，但目前尚不清楚视觉周期的异常反应是否参与了RPE的萎缩，从而导致视网膜病变的快速发生。在这里，我们报道了缺乏ATP结合盒转运蛋白4(ABCA4)和视黄醇脱氢酶8(RDH8)的小鼠，这两种蛋白质对光感受器的全视网膜清除至关重要，小鼠在早期就出现了严重的RPE/光感受器营养不良。这种表型包括脂褐素、玻璃体和基底板沉积，Bruchs膜增厚和脉络膜新生血管。重要的是，视觉功能障碍和视网膜病变的严重程度因光线而加重，但可通过视黄胺治疗而减轻，视黄胺是一种视觉周期抑制剂，可减缓全视网膜通过视觉周期的流动。这些发现提供了直接证据，表明在小鼠的视觉周期中，有毒凝结副产物的异常产生可以导致快速、进行性的视网膜退化。
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.