<i>Alu</i> complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity

Abstract

Long interspersed nuclear element-1 (L1)–mediated reverse transcription (RT) of <i>Alu</i> RNA into cytoplasmic <i>Alu</i> complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of <i>Alu</i> cDNA–induced cytotoxicity and its relevance to human disease are unknown. Here we report that <i>Alu</i> cDNA is highly enriched in the RPE of human eyes with geographic atrophy, an untreatable form of age-related macular degeneration. We demonstrate that the DNA sensor cGAS engages <i>Alu</i> cDNA to induce cytosolic mitochondrial DNA escape, which amplifies cGAS activation, triggering RPE degeneration via the inflammasome. The L1-extinct rice rat was resistant to <i>Alu</i> RNA–induced <i>Alu</i> cDNA synthesis and RPE degeneration, which were enabled upon L1-RT overexpression. Nucleoside RT inhibitors (NRTIs), which inhibit both L1-RT and inflammasome activity, and NRTI derivatives (Kamuvudines) that inhibit inflammasome, but not RT, both block <i>Alu</i> cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.