Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity. Article

Fukuda, Shinichi, Narendran, Siddharth, Varshney, Akhil et al. (2021). Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity. . SCIENCE ADVANCES, 7(40), eabj3658. 10.1126/sciadv.abj3658

cited authors

  • Fukuda, Shinichi; Narendran, Siddharth; Varshney, Akhil; Nagasaka, Yosuke; Wang, Shao-Bin; Ambati, Kameshwari; Apicella, Ivana; Pereira, Felipe; Fowler, Benjamin J; Yasuma, Tetsuhiro; Hirahara, Shuichiro; Yasuma, Reo; Huang, Peirong; Yerramothu, Praveen; Makin, Ryan D; Wang, Mo; Baker, Kirstie L; Marion, Kenneth M; Huang, Xiwen; Baghdasaryan, Elmira; Ambati, Meenakshi; Ambati, Vidya L; Banerjee, Daipayan; Bonilha, Vera L; Tolstonog, Genrich V; Held, Ulrike; Ogura, Yuichiro; Terasaki, Hiroko; Oshika, Tetsuro; Bhattarai, Deepak; Kim, Kyung Bo; Feldman, Sanford H; Aguirre, J Ignacio; Hinton, David R; Kerur, Nagaraj; Sadda, Srinivas R; Schumann, Gerald G; Gelfand, Bradley D; Ambati, Jayakrishna

authors

abstract

  • Long interspersed nuclear element-1 (L1)–mediated reverse transcription (RT) of Alu RNA into cytoplasmic Alu complementary DNA (cDNA) has been implicated in retinal pigmented epithelium (RPE) degeneration. The mechanism of Alu cDNA–induced cytotoxicity and its relevance to human disease are unknown. Here we report that Alu 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 Alu 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 Alu RNA–induced Alu 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 Alu cDNA toxicity, identifying inflammasome activation as the terminal effector of RPE degeneration.

publication date

  • October 1, 2021

published in

Digital Object Identifier (DOI)

Medium

  • Print-Electronic

start page

  • eabj3658

volume

  • 7

issue

  • 40