Abstract
Age-related macular degeneration (AMD) is the most common cause of vision loss in elderly individuals throughout the developed world. Inhibitors of vascular endothelial growth factor have been successfully used to treat choroidal neovascularization in late-stage AMD. The pathogenesis of early-stage AMD, however, remains largely unknown, impairing efforts to develop effective therapies that prevent progression to late-stage AMD. To address this, we performed comparative transcriptomics of macular and extramacular retinal pigmented epithelium-choroid (RPE-choroid) tissue from early-stage AMD patients. We found that expression of fatty acid desaturase 1 (FADS1), FADS2, and acetyl-CoA acetyltransferase 2 (ACAT2) is increased in macular but not extramacular tissue, possibly through activation of sterol regulatory element binding factor 1 (SREBF1). Consistent with this, we also found that expression of Fads1 is increased in RPE-choroid in a mouse model of early-stage AMD. In zebrafish, deletion of fads2, which encodes a protein that functions as both Fads1 and Fads2 in other species, enhanced apoptosis in the retina upon exposure to intense light. Similarly, pharmacological inhibition of Srebf1 enhanced apoptosis and reduced fads2 expression in zebrafish exposed to intense light. These results suggest that the SREBF1-FADS1/2 axis may be activated in macular RPE-choroid as a protective response during early-stage AMD and could thus be a therapeutic target for early-stage AMD.