Favret, Sandra, Rubic-Schneider, Tina, Carballido, Jose and Sapieha, Przemyslaw (2013) Deficiency in the Metabolite-Sensing Receptor SUCNR1 (GPR91) Leads to Outer Retinal Lesions akin to dry-Age-Related Macular Degeneration. Aging, 5 (6). pp. 427-444.

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 RPE-resident metabolite receptor, succinate receptor 1 (SUCNR1; G-Protein coupled Receptor-91 (GPR91), in preventing dry AMD-like lesions of the subretinal space. 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 largely confined to the Retinal Pigment Epithelium (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 pronounced buildup of lipid-bloated subretinal microglia. The accumulation of microglia in Sucnr1-/- 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

Item Type:	Article
Keywords:	immunometabolism
Date Deposited:	10 May 2016 23:45
Last Modified:	10 May 2016 23:45
URI:	https://oak.novartis.com/id/eprint/9309