title: 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.
authors.affiliation: Department of Ophthalmology, Hopital Maisonneuve-Rosemont Research Centre, University of Montreal, Montreal, Quebec, H1T 2M4, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Favret
authors.forename: Francois
authors.initials: F
authors.lastname: Binet
authors.forename: Eric
authors.initials: E
authors.lastname: Lapalme
authors.forename: Dominique
authors.initials: D
authors.lastname: Leboeuf
authors.forename: Jose
authors.initials: J
authors.lastname: Carbadillo
authors.forename: Tina
authors.initials: T
authors.lastname: Rubic
authors.forename: Emilie
authors.initials: E
authors.lastname: Picard
authors.forename: Gaelle
authors.initials: G
authors.lastname: Mawambo
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tetreault
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Joyal
authors.forename: Sylvain
authors.initials: S
authors.lastname: Chemtob
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: John Paul
authors.initials: JP
authors.lastname: Sangiovanni
authors.forename: Martin
authors.initials: M
authors.lastname: Guimond
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D016570:Bruch Membrane / Q000378:metabolism / Q000473:pathology; D004247:DNA / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology; D014644:Genetic Variation; D006801:Humans; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D012160:Retina / Q000378:metabolism
chemical_list: C531499:GPR91 protein, mouse; D043562:Receptors, G-Protein-Coupled; C557078:SUCNR1 protein, human; D004247:DNA