Cell non-autonomous retinal degeneration driven by endogenous DNA damage and senescence

Chronological age is the leading risk factor for age-related macular degeneration (AMD), the most common cause of irreversible blindness in the elderly. Blindness results from degeneration of retinal photoreceptors, specialized neurons. The retinal pigment epithelium (RPE) plays a critical role in maintaining photoreceptor health and dysfunction is a feature of AMD. Genomic instability, a primary hallmark of aging, is implicated in AMD pathogenesis, yet mechanistic studies are lacking. Here, we deleted the DNA repair gene Ercc1 in RPE to determine the impact of endogenous DNA damage on retinal structure and function. RPE of Ercc1 ^{RPE KO} mice displayed progressive morphological changes beginning at 3-months-of-age, including reduced cell number, cell enlargement, and multinucleation. Ercc1 ^{RPE KO} mice had progressive loss of visual function, accompanied by photoreceptor loss and choroid thinning. Transcriptomic analysis of Ercc1 ^{RPE KO} mouse RPE revealed upregulation of p53, apoptotic, senescence, interferon and TNFα pathways with downregulation of photoreceptor support and junction integrity at 3-months-of-age. Transcriptomic analysis of the neural retina showed activation of the DNA damage response, inflammatory and senescence pathways that transitioned to a sustained pro-inflammatory state with markers of oxidative stress and reduced mitochondrial metabolism at 6-months-of-age. Our data demonstrate that the RPE is vulnerable to genotoxic stress, which drives cell autonomous and non-autonomous senescence and death leading to retinal degeneration and blindness, features of AMD.