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

  1. Fukuda, Shinichi
  2. Narendran, Siddharth ORCID logo
  3. Varshney, Akhil
  4. Nagasaka, Yosuke
  5. Wang, Shao-Bin ORCID logo
  6. Ambati, Kameshwari
  7. Apicella, Ivana
  8. PEREIRA, FELIPE ORCID logo
  9. Fowler, Benjamin J.
  10. Yasuma, Tetsuhiro
  11. Hirahara, Shuichiro
  12. YASUMA, REO ORCID logo
  13. huang, peirong ORCID logo
  14. Yerramothu, Praveen
  15. Makin, Ryan ORCID logo
  16. Wang, Mo
  17. Baker, Kirstie ORCID logo
  18. Marion, Ken ORCID logo
  19. Huang, Xiwen
  20. Baghdasaryan, Elmira
  21. Ambati, Meenakshi
  22. Ambati, Vidya L.
  23. Banerjee, Daipayan
  24. Bonilha, Vera ORCID logo
  25. Tolstonog, Genrich ORCID logo
  26. Held, Ulrike
  27. Ogura, Yuichiro ORCID logo
  28. Terasaki, Hiroko ORCID logo
  29. Oshika, Tetsuro ORCID logo
  30. Bhattarai, Deepak
  31. Kim, Kyung Bo ORCID logo
  32. Feldman, Sanford H.
  33. Aguirre, Jose ORCID logo
  34. Hinton, David R.
  35. Kerur, Nagaraj
  36. Sadda, Srinivas R.
  37. Schumann, Gerald ORCID logo
  38. Gelfand, Bradley ORCID logo
  39. Ambati, Jayakrishna ORCID logo

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1000 Titel
  • Alu complementary DNA is enriched in atrophic macular degeneration and triggers retinal pigmented epithelium toxicity via cytosolic innate immunity
1000 Autor/in
  1. Fukuda, Shinichi |
  2. Narendran, Siddharth |
  3. Varshney, Akhil |
  4. Nagasaka, Yosuke |
  5. Wang, Shao-Bin |
  6. Ambati, Kameshwari |
  7. Apicella, Ivana |
  8. PEREIRA, FELIPE |
  9. Fowler, Benjamin J. |
  10. Yasuma, Tetsuhiro |
  11. Hirahara, Shuichiro |
  12. YASUMA, REO |
  13. huang, peirong |
  14. Yerramothu, Praveen |
  15. Makin, Ryan |
  16. Wang, Mo |
  17. Baker, Kirstie |
  18. Marion, Ken |
  19. Huang, Xiwen |
  20. Baghdasaryan, Elmira |
  21. Ambati, Meenakshi |
  22. Ambati, Vidya L. |
  23. Banerjee, Daipayan |
  24. Bonilha, Vera |
  25. Tolstonog, Genrich |
  26. Held, Ulrike |
  27. Ogura, Yuichiro |
  28. Terasaki, Hiroko |
  29. Oshika, Tetsuro |
  30. Bhattarai, Deepak |
  31. Kim, Kyung Bo |
  32. Feldman, Sanford H. |
  33. Aguirre, Jose |
  34. Hinton, David R. |
  35. Kerur, Nagaraj |
  36. Sadda, Srinivas R. |
  37. Schumann, Gerald |
  38. Gelfand, Bradley |
  39. Ambati, Jayakrishna |
1000 Erscheinungsjahr 2021
1000 Publikationstyp
  1. Artikel |
1000 Online veröffentlicht
  • 2021-09-29
1000 Erschienen in
1000 Quellenangabe
  • 7(40):eabj3658
1000 FRL-Sammlung
1000 Copyrightjahr
  • 2021
1000 Lizenz
1000 Verlagsversion
  • https://doi.org/10.1126/sciadv.abj3658 |
  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8480932/ |
1000 Ergänzendes Material
  • https://www.science.org/doi/10.1126/sciadv.abj3658#supplementary-materials |
1000 Publikationsstatus
1000 Begutachtungsstatus
1000 Sprache der Publikation
1000 Abstract/Summary
  • 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.
1000 Sacherschließung
gnd 4210043-4 Makuladegeneration
1000 Fächerklassifikation (DDC)
1000 Liste der Beteiligten
  1. https://frl.publisso.de/adhoc/uri/RnVrdWRhLCBTaGluaWNoaQ==|https://orcid.org/0000-0002-9220-8049|https://frl.publisso.de/adhoc/uri/VmFyc2huZXksIEFraGls|https://frl.publisso.de/adhoc/uri/TmFnYXNha2EsIFlvc3VrZQ==|https://orcid.org/0000-0001-5860-3777|https://frl.publisso.de/adhoc/uri/QW1iYXRpLCBLYW1lc2h3YXJp|https://frl.publisso.de/adhoc/uri/QXBpY2VsbGEsIEl2YW5h|https://orcid.org/0000-0001-8884-2816|https://frl.publisso.de/adhoc/uri/Rm93bGVyLCBCZW5qYW1pbiBKLg==|https://frl.publisso.de/adhoc/uri/WWFzdW1hLCBUZXRzdWhpcm8=|https://frl.publisso.de/adhoc/uri/SGlyYWhhcmEsIFNodWljaGlybw==|https://orcid.org/0000-0001-6205-1151|https://orcid.org/0000-0003-2793-1473|https://frl.publisso.de/adhoc/uri/WWVycmFtb3RodSwgUHJhdmVlbg==|https://orcid.org/0000-0002-8804-4125|https://frl.publisso.de/adhoc/uri/V2FuZywgTW8=|https://orcid.org/0000-0003-3953-4352|https://orcid.org/0000-0003-1275-5729|https://frl.publisso.de/adhoc/uri/SHVhbmcsIFhpd2Vu|https://frl.publisso.de/adhoc/uri/QmFnaGRhc2FyeWFuLCBFbG1pcmE=|https://frl.publisso.de/adhoc/uri/QW1iYXRpLCBNZWVuYWtzaGk=|https://frl.publisso.de/adhoc/uri/QW1iYXRpLCBWaWR5YSBMLg==|https://frl.publisso.de/adhoc/uri/QmFuZXJqZWUsIERhaXBheWFu|https://orcid.org/0000-0002-6166-5124|https://orcid.org/0000-0002-5560-4157|https://frl.publisso.de/adhoc/uri/SGVsZCwgVWxyaWtl|https://orcid.org/0000-0003-0430-5330|https://orcid.org/0000-0003-2879-4220|https://orcid.org/0000-0002-9071-7018|https://frl.publisso.de/adhoc/uri/QmhhdHRhcmFpLCBEZWVwYWs=|https://orcid.org/0000-0003-4744-2466|https://frl.publisso.de/adhoc/uri/RmVsZG1hbiwgU2FuZm9yZCBILg==|https://orcid.org/0000-0001-8100-5839|https://frl.publisso.de/adhoc/uri/SGludG9uLCBEYXZpZCBSLg==|https://frl.publisso.de/adhoc/uri/S2VydXIsIE5hZ2FyYWo=|https://frl.publisso.de/adhoc/uri/U2FkZGEsIFNyaW5pdmFzIFIu|https://orcid.org/0000-0003-1400-3424|https://orcid.org/0000-0003-4619-9409|https://orcid.org/0000-0003-1622-6365
1000 Label
1000 Förderer
  1. National Institutes of Health |
  2. John Templeton Foundation |
  3. Japan Society for the Promotion of Science |
  4. Japan Eye Bank Association |
  5. Arnold and Mabel Beckman Initiative for Macular Research |
  6. Association for Research in Vision and Ophthalmology |
  7. Fight for Sight |
  8. Research to Prevent Blindness |
  9. BrightFocus Foundation |
  10. Owens Family Foundation |
1000 Fördernummer
  1. DP1GM114862; R01EY022238; R01EY024068; R01EY028027; R01EY029799; R01EY031039; K99EY024336; R00EY024336; R01AI48741; R21EY030651; T32HL091812; UL1RR033173; R01EY027750; P30EY025585; R01EY001545; R01EY028027; R01EY031039; R01EY032512
  2. 60763
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  5. -
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1000 Förderprogramm
  1. -
  2. -
  3. -
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  5. -
  6. -
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  10. -
1000 Dateien
1000 Förderung
  1. 1000 joinedFunding-child
    1000 Förderer National Institutes of Health |
    1000 Förderprogramm -
    1000 Fördernummer DP1GM114862; R01EY022238; R01EY024068; R01EY028027; R01EY029799; R01EY031039; K99EY024336; R00EY024336; R01AI48741; R21EY030651; T32HL091812; UL1RR033173; R01EY027750; P30EY025585; R01EY001545; R01EY028027; R01EY031039; R01EY032512
  2. 1000 joinedFunding-child
    1000 Förderer John Templeton Foundation |
    1000 Förderprogramm -
    1000 Fördernummer 60763
  3. 1000 joinedFunding-child
    1000 Förderer Japan Society for the Promotion of Science |
    1000 Förderprogramm -
    1000 Fördernummer -
  4. 1000 joinedFunding-child
    1000 Förderer Japan Eye Bank Association |
    1000 Förderprogramm -
    1000 Fördernummer -
  5. 1000 joinedFunding-child
    1000 Förderer Arnold and Mabel Beckman Initiative for Macular Research |
    1000 Förderprogramm -
    1000 Fördernummer -
  6. 1000 joinedFunding-child
    1000 Förderer Association for Research in Vision and Ophthalmology |
    1000 Förderprogramm -
    1000 Fördernummer -
  7. 1000 joinedFunding-child
    1000 Förderer Fight for Sight |
    1000 Förderprogramm -
    1000 Fördernummer -
  8. 1000 joinedFunding-child
    1000 Förderer Research to Prevent Blindness |
    1000 Förderprogramm -
    1000 Fördernummer -
  9. 1000 joinedFunding-child
    1000 Förderer BrightFocus Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
  10. 1000 joinedFunding-child
    1000 Förderer Owens Family Foundation |
    1000 Förderprogramm -
    1000 Fördernummer -
1000 Objektart article
1000 Beschrieben durch
1000 @id frl:6431813.rdf
1000 Erstellt am 2022-02-28T11:26:31.722+0100
1000 Erstellt von 323
1000 beschreibt frl:6431813
1000 Bearbeitet von 25
1000 Zuletzt bearbeitet Wed Mar 09 09:21:57 CET 2022
1000 Objekt bearb. Wed Mar 09 09:21:44 CET 2022
1000 Vgl. frl:6431813
1000 Oai Id
  1. oai:frl.publisso.de:frl:6431813 |
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