Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions.
Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions.
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DOI：
10.18632/aging.100563
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发表时间：
2013-06
期刊：
影响因子：
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通讯作者：
Sapieha P
中科院分区：
文献类型：
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作者：
Favret S;Binet F;Lapalme E;Leboeuf D;Carbadillo J;Rubic T;Picard E;Mawambo G;Tetreault N;Joyal JS;Chemtob S;Sennlaub F;Sangiovanni JP;Guimond M;Sapieha P
视网膜相关性黄斑变性（AMD）是西方世界的主要致盲原因。迄今为止，其分子发病机制以及导致视网膜变性的事件序列在很大程度上仍不明确。虽然脉络膜新生血管的侵入是导致视力丧失的主要机制，但早期的干性形式可能伴随着它。在此，我们提供了视网膜色素上皮（RPE）驻留代谢物受体琥珀酸受体1（SUCNR 1）、G蛋白偶联受体91（GPR 91）在预防外层视网膜的干性AMD样病变中的保护作用的第一个证据。对925名地图状萎缩患者和1199名无AMD的同龄人进行的遗传分析显示，发生与SUCNR 1基因内含子变异相关的地图状萎缩的风险增加。在小鼠中，在RPE以及小胶质细胞中观察到SUCNR 1的外视网膜表达，并且随着年龄的增长而逐渐减少。因此，Sucnr 1 −/−小鼠表现出过早的视网膜下营养不良的迹象，伴随着氧化LDL的积累、布鲁赫膜的异常增厚和视网膜下小胶质细胞的积聚。Sucnr 1缺陷小鼠中小胶质细胞的积累可能是由RPE对氧化脂质的低效清除引发的，因为将野生型小胶质细胞骨髓转移到Sucnr 1 −/−小鼠中并没有挽救病理表型，并且野生型和对照小鼠之间的全身脂解作用是等同的。我们的研究结果表明，SUCNR 1的缺陷是干性AMD发病机制的一个可能的促成因素，从而扩大了我们对这一临床未满足需求的理解。
Age-related macular degeneration (AMD) is a prominent cause of blindness in the Western world. To date, its molecular pathogenesis as well as the sequence of events leading to retinal degeneration remain largely ill-defined. While the invasion of choroidal neovasculature in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form may accompany it. Here we provide the first evidence for the protective role of the Retinal Pigment Epithelium (RPE)-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the outer retina. Genetic analysis of 925 patients with geographic atrophy and 1199 AMD-free peers revealed an increased risk of developing geographic atrophy associated with intronic variants in the SUCNR1 gene. In mice, outer retinal expression of SUCNR1 is observed in the RPE as well as microglial cells and decreases progressively with age. Accordingly, Sucnr1−/− mice show signs of premature sub-retinal dystrophy with accumulation of oxidized-LDL, abnormal thickening of Bruch's membrane and a buildup of subretinal microglia. The accumulation of microglia in Sucnr1-deficient mice is likely triggered by the inefficient clearance of oxidized lipids by the RPE as bone marrow transfer of wild-type microglia into Sucnr1−/− mice did not salvage the patho-phenotype and systemic lipolysis was equivalent between wild-type and control mice. Our findings suggest that deficiency in SUCNR1 is a possible contributing factor to the pathogenesis of dry AMD and thus broaden our understanding of this clinically unmet need.