Ablation of the riboflavin-binding protein retbindin reduces flavin levels and leads to progressive and dose-dependent degeneration of rods and cones
Ablation of the riboflavin-binding protein retbindin reduces flavin levels and leads to progressive and dose-dependent degeneration of rods and cones
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DOI：
10.1074/jbc.m117.785105
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发表时间：
2017-12-22
影响因子：
4.8
通讯作者：
Naash, Muna I.
中科院分区：
文献类型：
--
作者：
Kelley, Ryan A.;Al-Ubaidi, Muayyad R.;Naash, Muna I.
神经视网膜和视网膜色素上皮(RPE)之间的界面对几个过程至关重要，包括视觉色素再生和视网膜附着到RPE上。它最重要的功能之一是光感受器和RPE之间的代谢物交换，因为光感受器细胞有非常高的能量需求，主要由氧化代谢来满足。核黄素(RF)辅因子黄素腺嘌呤二核苷酸(FAD)和黄素单核苷酸(FMN)是参与氧化代谢的两个关键辅因子。我们先前已经证明，视黄醇结合蛋白是一种光感受器特异的RF结合蛋白，仅在视杆细胞中表达，存在于RPE和光感受器外节之间的光感受器间基质中。在这里，我们表明，在小鼠中，视黄醇结合素消融导致视网膜表型，其特征是视杆和视锥感光细胞功能在出生后120天就呈时间和剂量依赖性的下降。虽然在所有日龄都观察到轻微的视网膜超微结构缺陷，但在240日龄时，光感受器核明显减少(类似于36.8%的视杆细胞和19.9%的视锥细胞)。有趣的是，在变性开始之前，FAD和FMN水平显著降低(类似于46.1%的FAD和类似于45%的FMN)。这些发现表明，这些黄素水平的降低导致细胞内机制的破坏，导致光感受器细胞死亡。总之，我们的结果表明，视黄素在神经视网膜中的获得和保留中起关键作用，这为进一步研究视黄素在视网膜退行性疾病模型中光感受器细胞死亡中的作用奠定了基础。
The interface between the neural retina and the retinal pigment epithelium (RPE) is critical for several processes, including visual pigment regeneration and retinal attachment to the RPE. One of its most important functions is the exchange of metabolites between the photoreceptors and RPE because photoreceptor cells have very high energy demands, largely satisfied by oxidative metabolism. The riboflavin (RF) cofactors, flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), are two key cofactors involved in oxidative metabolism. We have previously shown that retbindin is a photoreceptor-specific RF-binding protein exclusively expressed in the rods and present in the interphotoreceptor matrix at the interface between the RPE and photoreceptor outer segments. Here, we show that retbindin ablation in mice causes a retinal phenotype characterized by time- and dose-dependent declines in rod and cone photoreceptor functions as early as 120 days of age. Whereas minor retinal ultrastructural defects were observed at all ages examined, a significant decline occurred in photoreceptor nuclei at 240 days of age (similar to 36.8% rods and similar to 19.9% cones). Interestingly, significant reductions in FAD and FMN levels were observed before the onset of degeneration (similar to 46.1% FAD and similar to 45% FMN). These findings suggest that the reduced levels of these flavins result in the disruption of intracellular mechanisms, leading to photoreceptor cell death. Altogether, our results suggest that retbindin is a key player in the acquisition and retention of flavins in the neural retina, warranting future investigation into retbindin's role in photoreceptor cell death in models of retinal degenerative disorders.