The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration
The Rpe65 Leu450Met variation increases retinal resistance against light-induced degeneration by slowing rhodopsin regeneration
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DOI：
10.1523/jneurosci.21-01-00053.2001
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Grimm, C
中科院分区：
文献类型：
--
作者：
Wenzel, A;Remé, CE;Grimm, C
过度的光线会导致视网膜变性，并且可能是加速视网膜营养不良和年龄相关疾病的环境辅助因素。在啮齿动物模型中，视网膜的光损伤易感性（LDS）由遗传决定。在两个小鼠品系，具有不同程度的LDS，Leu 450 Met的色素上皮蛋白RPE 65的变化，最近被证明与低LDS共分离。由于光损伤是视紫红质介导的，并且RPE 65对于视紫红质在视觉周期中的再生是必不可少的，因此我们分析了四种小鼠品系中视紫红质代谢和LDS的这种变化。我们发现，在以前的断言相反，LDS不相关的最大视网膜视紫红质含量存在暗适应后。相反，LDS与视紫红质再生动力学呈正相关，这决定了光暴露期间视紫红质的可用性。光损伤发生后，吸收的阈值剂量的光子，从而快速再生，如在这两个菌株中观察到的Leu在位置450的RPE 65，与发生光感受器细胞凋亡后短时间曝光。相比之下，具有Rpe 65的Leu 450 Met变异的小鼠以缓慢的动力学再生视紫红质，并表现出对光诱导的视网膜变性的抵抗力增加。在这些小鼠中，RPE 65蛋白水平通过转录后机制降低。F-1杂交小鼠，携带一个正常的和一个变异Rpe 65基因，具有中间水平的相应蛋白质，并显示中间视紫红质再生动力学和中间LDS。因此，Rpe 65的两个变体都没有产生主导作用。
Excessive light can cause retinal degeneration and may be an environmental cofactor accelerating retinal dystrophies and age-related diseases. In rodent models, the light damage susceptibility (LDS) of the retina is determined genetically. In two mouse strains, with different degrees of LDS, a Leu450Met variation in the pigment epithelial protein RPE65 was shown recently to cosegregate with low LDS. Because light damage is rhodopsin-mediated, and RPE65 is essential for the regeneration of rhodopsin in the visual cycle, we analyzed this variation regarding rhodopsin metabolism and LDS in four mouse strains. We found that, in contrast to previous assertions, LDS does not correlate with the maximal retinal content of rhodopsin present after dark adaptation. Instead, LDS correlated positively with the kinetics of rhodopsin regeneration, which determine rhodopsin availability during light exposure. Light damage occurred after absorption of a threshold dose of photons and thus fast regeneration, as observed in those two strains having Leu at position 450 of RPE65, was correlated with the occurrence of photoreceptor apoptosis after short exposure. In contrast, mice with the Leu450Met variation of Rpe65 regenerated rhodopsin with slow kinetics and showed an increased resistance to light-induced retinal degeneration. In these mice, RPE65 protein levels were reduced by a post-transcriptional mechanism. F-1 hybrid mice, carrying one normal and one variant Rpe65 gene, had intermediate levels of the corresponding protein and showed intermediate rhodopsin regeneration kinetics and an intermediate LDS. Thus, none of the two variants of Rpe65 had a dominant effect.