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

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.
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Contributor : Emilie Picard Connect in order to contact the contributor
Submitted on : Friday, October 30, 2020 - 10:24:18 AM
Last modification on : Wednesday, February 2, 2022 - 3:38:56 AM

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Sandra Favret, Francois Binet, Eric Lapalme, Dominique Leboeuf, Jose Carbadillo, et al.. Deficiency in the metabolite receptor SUCNR1 (GPR91) leads to outer retinal lesions. Aging, Impact Journals, 2013, 5 (6), pp.427-444. ⟨10.18632/aging.100563⟩. ⟨inserm-02983636⟩



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