The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model
The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model
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DOI：
10.1073/pnas.0708714104
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发表时间：
2007-12-04
影响因子：
11.1
通讯作者：
Sparrow, Janet R.
中科院分区：
文献类型：
--
作者：
Kim, So R.;Jang, Young P.;Sparrow, Janet R.
以脂褐素形式积聚在视网膜色素上皮细胞中的双视黄醇色素与遗传性和年龄相关的视网膜疾病有关。除了A2E和相关的顺式异构体之外，我们之前证明全陷阱-视黄醛的两个分子的缩合导致形成质子化希夫碱缀合物，全陷阱-视黄醛二聚体-磷脂酰乙醇胺。在这里，我们报告了人类和小鼠视网膜色素上皮中相关色素、全陷阱-视网膜晚餐-乙醇胺和未结合的全视网膜晚餐的表征。在隐性 Stargardt 黄斑变性模型 Abcr(-/-) 小鼠的眼杯中，全陷阱-视网膜晚餐-磷脂酰乙醇胺相对于野生型有所增加，并且比 A2E 更丰富。 Abcr(-/-) 小鼠中全陷阱-视网膜二聚体系列的总色素（全陷阱-视网膜二聚体-磷脂酰乙醇胺、全陷阱-视网膜二聚体-乙醇胺和全陷阱-视网膜二聚体的总和）随着年龄的增长而增加，并受到 Rpe65 中氨基酸变体的调节。在体外测定中，全经视网膜正餐-磷脂酰乙醇胺的酶介导水解产生全经视网膜正餐-乙醇胺，并且全陷阱-视网膜正餐-乙醇胺的希夫碱氮的质子化/去质子化是pH依赖性的。未结合的全陷阱-视网膜晚餐是比A2E更有效的单线态氧发生器，并且全陷阱-视网膜晚餐系列与单线态氧的反应性比A2E更强。通过分析色谱特性、紫外可见光谱以及质谱，在 Abcr(-/-) 小鼠中检测到单氧和双氧全陷阱视网膜晚餐光产物。后者的发现对于了解视网膜色素上皮细胞脂褐素的副作用具有重要意义。
The bis-retinoid pigments that accumulate in retinal pigment epithelial cells as lipofuscin are associated with inherited and age-related retinal disease. In addition to A2E and related cis isomers, we previously showed that condensation of two molecules of all-traps-retinal leads to the formation of a protonated Schiff base conjugate, all-traps-retinal dinner-phosphatidylethanolamine. Here we report the characterization of the related pigments, all-traps-retinal dinner-ethanolamine and unconjugated all-transretinal dinner, in human and mouse retinal pigment epithelium. In eyecups of Abcr(-/-) mice, a model of recessive Stargardt macular degeneration, all-traps-retinal dinner-phosphatidylethanolamine was increased relative to wild type and was more abundant than A2E. Total pigment of the all-traps-retinal dimer series (sum of all-traps-retinal dinner-phosphatidylethanolamine, all-traps-retinal dinner-ethanolamine, and all-traps-retinal dimer) increased with age in Abcr(-/-) mice and was modulated by amino acid variants in Rpe65. In in vitro assays, enzyme-mediated hydrolysis of all-transretinal dinner-phosphatidylethanolamine generated all-transretinal dinner-ethanolamine, and protonation/deprotonation of the Schiff base nitrogen of all-traps-retinal dinner-ethanolamine was pH-dependent. Unconjugated all-traps-retinal dinner was a more efficient generator of singlet oxygen than A2E, and the all-traps-retinal dinner series was more reactive with singlet oxygen than was A2E. By analyzing chromatographic properties and UV-visible spectra together with mass spectrometry, mono- and bis-oxygenated all-traps-retinal dinner photoproducts were detected in Abcr(-/-) mice. The latter findings are significant to an understanding of the adverse effects of retinal pigment epithelial cell lipofuscin.