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Alu 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 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.

SUBMITTER: Fukuda S

PROVIDER: S-EPMC8480932 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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

Fukuda Shinichi S Narendran Siddharth S Varshney Akhil A Nagasaka Yosuke Y Wang Shao-Bin SB Ambati Kameshwari K Apicella Ivana I Pereira Felipe F Fowler Benjamin J BJ Yasuma Tetsuhiro T Hirahara Shuichiro S Yasuma Reo R Huang Peirong P Yerramothu Praveen P Makin Ryan D RD Wang Mo M Baker Kirstie L KL Marion Kenneth M KM Huang Xiwen X Baghdasaryan Elmira E Ambati Meenakshi M Ambati Vidya L VL Banerjee Daipayan D Bonilha Vera L VL Tolstonog Genrich V GV Held Ulrike U Ogura Yuichiro Y Terasaki Hiroko H Oshika Tetsuro T Bhattarai Deepak D Kim Kyung Bo KB Feldman Sanford H SH Aguirre J Ignacio JI Hinton David R DR Kerur Nagaraj N Sadda Srinivas R SR Schumann Gerald G GG Gelfand Bradley D BD Ambati Jayakrishna J

Science advances 20210929 40

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 t ...[more]

PMID: 34586848

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Project description:PurposeLoss of photoreceptors in atrophic age-related macular degeneration results in severe visual impairment, although some peripheral vision is retained. To restore central vision without compromising the residual peripheral field, we developed a wireless photovoltaic retinal implant (PRIMA; Pixium Vision, Paris, France) in which pixels convert images projected from video glasses using near-infrared light into electric current to stimulate the nearby inner retinal neurons.DesignWe carried out a first-in-human clinical trial to test the safety and efficacy of the prosthesis in patients with geographic atrophy (ClinicalTrials.gov identifier, NCT03333954).ParticipantsFive patients with geographic atrophy zone of at least 3 optic disc diameters, no foveal light perception, and best-corrected visual acuity of 20/400 to 20/1000 in the worse-seeing study eye.MethodsThe 2-mm wide, 30-μm thick chip, containing 378 pixels (each 100 μm in diameter), was implanted subretinally in the area of atrophy (absolute scotoma).Main outcome measuresAnatomic outcomes were assessed with fundus photography and OCT for up to 12 months of follow-up. Prosthetic vision was assessed by mapping light perception, bar orientation, letter recognition, and Landolt C acuity.ResultsIn all patients, the prosthesis was implanted successfully under the macula, although in 2 patients, it was implanted in unintended locations: within the choroid and off center by 2 mm. All 5 patients could perceive white-yellow prosthetic visual patterns with adjustable brightness in the previous scotomata. The 3 with optimal placement of the implant demonstrated prosthetic acuity of 20/460 to 20/550, and the patient with the off-center implant demonstrated 20/800 acuity. Residual natural acuity did not decrease after implantation in any patient.ConclusionsImplantation of the PRIMA did not decrease the residual natural acuity, and it restored visual sensitivity in the former scotoma in each of the 5 patients. In 3 patients with the proper placement of the chip, prosthetic visual acuity was only 10% to 30% less than the level expected from the pixel pitch (20/420). Therefore, the use of optical or electronic magnification in the glasses as well as smaller pixels in future implants may improve visual acuity even further.

Dataset Information

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

Publications

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

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