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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; 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.
Afiliação
  • Fukuda S; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Narendran S; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Varshney A; Department of Ophthalmology, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan.
  • Nagasaka Y; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Wang SB; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Ambati K; Aravind Eye Hospital System, Madurai, India.
  • Apicella I; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Pereira F; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Fowler BJ; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Yasuma T; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Hirahara S; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Yasuma R; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Huang P; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Yerramothu P; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Makin RD; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Wang M; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Baker KL; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Marion KM; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Huang X; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Baghdasaryan E; Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil.
  • Ambati M; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY, USA.
  • Ambati VL; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Banerjee D; Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil.
  • Bonilha VL; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Tolstonog GV; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Held U; Department of Ophthalmology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
  • Ogura Y; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Terasaki H; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Oshika T; Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
  • Bhattarai D; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Kim KB; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Feldman SH; Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
  • Aguirre JI; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Hinton DR; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Kerur N; Center for Advanced Vision Science, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Sadda SR; Department of Ophthalmology, University of Virginia School of Medicine, Charlottesville, VA, USA.
  • Schumann GG; Doheny Eye Institute, Los Angeles, CA, USA.
  • Gelfand BD; Doheny Eye Institute, Los Angeles, CA, USA.
  • Ambati J; Doheny Eye Institute, Los Angeles, CA, USA.
Sci Adv ; 7(40): eabj3658, 2021 Oct.
Article em En | MEDLINE | ID: mdl-34586848
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 cDNA­induced 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 RNA­induced 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.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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XML
PubMed Links
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2021 Tipo de documento: Article