Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions

Sandra Favret,Francois Binet,Gaelle Mawambo,Eric Lapalme,Martin Guimond,Przemyslaw Sapieha,Sylvain Chemtob,Dominique Leboeuf,Emilie Picard,Tina Rubic,Jean-Sebastien Joyal,Jose Carbadillo,Florian Sennlaub,Nicolas Tetreault,John Paul Sangiovanni

doi:10.18632/aging.100563

Abstract

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 neovessels in the retina is the primary mechanism that precipitates loss of sight, an earlier dry form precedes 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 theSUCNR1 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.

Highlights

Age-related macular degeneration is the leading cause of blindness in developed countries, affecting over 10 million individuals in North America itself and a proportional number in Europe [1,2,3]
Promoter regions tend to be DNasesensitive. rs9811297 is in nearly complete linkage disequilibrium with at least two variants resident in the 5' untranslated region (UTR) of SUCNR1
In this study, using a combination of human genetic analysis and mouse models, we provide evidence for the prospective involvement of SUCNR1 (GPR91) in preventing premature subretinal AMD-like lesions

Summary

Introduction

Age-related macular degeneration is the leading cause of blindness in developed countries, affecting over 10 million individuals in North America itself and a proportional number in Europe [1,2,3]. The aging of ‘‘baby boomers’’ will lead to a doubling of the population of 65 years of age or older by 2031 and significantly increase the number of affected individuals. The dry form of AMD is characterized by drusen which are stereotypic extracellular deposits between the RPE basal lamina and the inner collagenous layer of Bruch’s membrane [7]. Drusen can result from membranous debris shed from the basal surface of the RPE and eventually lead, over time, to large areas of retinal degeneration called geographic atrophy (GA) [5, 7]. It is believed that drusenoid deposits (i.e. reticular pseudodrusen) can be found on the apical side of RPE and contribute to AMD progression [8]

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