Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration.

Autor:	Fukuda S; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, University of Tsukuba, Ibaraki 305-8575, Japan., Varshney A; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Fowler BJ; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536., Wang SB; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Narendran S; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Aravind Eye Hospital System, Madurai 625020, India., Ambati K; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Yasuma T; Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536.; Department of Ophthalmology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan., Magagnoli J; Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.; Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208., Leung H; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Hirahara S; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Nagasaka Y; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Yasuma R; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan., Apicella I; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Pereira F; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil., Makin RD; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Magner E; Department of Computer Science, University of Kentucky, Lexington, KY 40536., Liu X; Department of Computer Science, University of Kentucky, Lexington, KY 40536., Sun J; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Wang M; Doheny Eye Institute, Los Angeles, CA 90033., Baker K; Doheny Eye Institute, Los Angeles, CA 90033., Marion KM; Doheny Eye Institute, Los Angeles, CA 90033., Huang X; Department of Computer Science, University of Kentucky, Lexington, KY 40536., Baghdasaryan E; Doheny Eye Institute, Los Angeles, CA 90033.; Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Ambati M; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Center for Digital Image Evaluation, Charlottesville, VA 22901., Ambati VL; Center for Digital Image Evaluation, Charlottesville, VA 22901., Pandey A; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Pandya L; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Cummings T; Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.; Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208., Banerjee D; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Huang P; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Yerramothu P; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Tolstonog GV; Department of Otolaryngology-Head and Neck Surgery, University Hospital of Lausanne, 1011 Lausanne, Switzerland., Held U; Department of Medical Biotechnology, Paul Ehrlich Institute, 63225 Langen, Germany., Erwin JA; The Lieber Institute for Brain Development, School of Medicine, Johns Hopkins University, Baltimore, MD 21205., Paquola ACM; The Lieber Institute for Brain Development, School of Medicine, Johns Hopkins University, Baltimore, MD 21205., Herdy JR; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037., Ogura Y; Department of Ophthalmology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan., Terasaki H; Department of Ophthalmology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan., Oshika T; Department of Ophthalmology, University of Tsukuba, Ibaraki 305-8575, Japan., Darwish S; Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618.; Organometallic and Organometalloid Chemistry Department, National Research Centre, Giza 12622, Egypt., Singh RK; Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618., Mozaffari S; Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618., Bhattarai D; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536., Kim KB; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536., Hardin JW; Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.; Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC 29208., Bennett CL; Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.; Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208.; Center for Medication Safety and Efficacy, College of Pharmacy, University of South Carolina, Columbia, SC 29208., Hinton DR; Department of Ophthalmology, University of Southern California Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033., Hanson TE; Medtronic, Inc., Minneapolis, MN 55432.; Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455., Röver C; Department of Medical Statistics, University Medical Center Göttingen, D-37073 Göttingen, Germany., Parang K; Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618., Kerur N; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908., Liu J; Department of Computer Science, University of Kentucky, Lexington, KY 40536., Werner BC; Department of Orthopaedic Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908., Sutton SS; Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.; Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208., Sadda SR; Doheny Eye Institute, Los Angeles, CA 90033.; Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Schumann GG; Department of Medical Biotechnology, Paul Ehrlich Institute, 63225 Langen, Germany., Gelfand BD; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22908., Gage FH; Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037; gage@salk.edu ja9qr@virginia.edu., Ambati J; Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908; gage@salk.edu ja9qr@virginia.edu.; Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908.; Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Feb 09; Vol. 118 (6).
DOI:	10.1073/pnas.2022751118
Abstrakt:	Alu retroelements propagate via retrotransposition by hijacking long interspersed nuclear element-1 (L1) reverse transcriptase (RT) and endonuclease activities. Reverse transcription of Alu RNA into complementary DNA (cDNA) is presumed to occur exclusively in the nucleus at the genomic integration site. Whether Alu cDNA is synthesized independently of genomic integration is unknown. Alu RNA promotes retinal pigmented epithelium (RPE) death in geographic atrophy, an untreatable type of age-related macular degeneration. We report that Alu RNA-induced RPE degeneration is mediated via cytoplasmic L1-reverse-transcribed Alu cDNA independently of retrotransposition. Alu RNA did not induce cDNA production or RPE degeneration in L1-inhibited animals or human cells. Alu reverse transcription can be initiated in the cytoplasm via self-priming of Alu RNA. In four health insurance databases, use of nucleoside RT inhibitors was associated with reduced risk of developing atrophic macular degeneration (pooled adjusted hazard ratio, 0.616; 95% confidence interval, 0.493-0.770), thus identifying inhibitors of this Alu replication cycle shunt as potential therapies for a major cause of blindness. Competing Interests: Competing interest statement: J.A. is a co-founder of iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics, and has been a consultant for Allergan, Biogen, Boehringer-Ingelheim, Immunovant, Janssen, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences unrelated to this work. J.A., B.D.G., B.J.F., S.N., K.A., S.-b.W., I.A., M.A., F.P., N.K., and S.F. are named as inventors on patent applications on macular degeneration filed by the University of Virginia or the University of Kentucky. J.W.H. has received consulting fees from Celgene Corporation unrelated to this work. S.S.S. has received research grants from Boehringer Ingelheim, Gilead Sciences, Portola Pharmaceuticals, and United Therapeutics unrelated to this work. J.A. and B.D.G. are co-founders of DiceRx.
Databáze:	MEDLINE
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