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

Affiliation

Fukuda S(1)(2)(3), Varshney A(1)(2), Fowler BJ(4), Wang SB(1)(2), Narendran S(1)(2)(5), Ambati K(1)(2), Yasuma T(4)(6), Magagnoli J(7)(8), Leung H(1)(2), Hirahara S(1)(2)(9), Nagasaka Y(1)(2), Yasuma R(1)(2)(6), Apicella I(1)(2), Pereira F(1)(2)(10), Makin RD(1)(2), Magner E(11), Liu X(11), Sun J(1)(2), Wang M(12), Baker K(12), Marion KM(12), Huang X(11), Baghdasaryan E(12)(13), Ambati M(1)(2)(14), Ambati VL(14), Pandey A(1)(2), Pandya L(1)(2), Cummings T(7)(8), Banerjee D(1)(2), Huang P(1)(2), Yerramothu P(1)(2), Tolstonog GV(15), Held U(16), Erwin JA(17), Paquola ACM(17), Herdy JR(18), Ogura Y(9), Terasaki H(6), Oshika T(3), Darwish S(19)(20), Singh RK(19), Mozaffari S(19), Bhattarai D(21), Kim KB(21), Hardin JW(7)(22), Bennett CL(7)(8)(23), Hinton DR(24)(25), Hanson TE(26)(27), Röver C(28), Parang K(19), Kerur N(1)(2)(29)(30), Liu J(11), Werner BC(31), Sutton SS(7)(8), Sadda SR(12)(13), Schumann GG(16), Gelfand BD(1)(2)(32), Gage FH(33), Ambati J(34)(2)(30)(35).
Author information:
(1)Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(2)Department of Ophthalmology, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(3)Department of Ophthalmology, University of Tsukuba, Ibaraki 305-8575, Japan.
(4)Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40536.
(5)Aravind Eye Hospital System, Madurai 625020, India.
(6)Department of Ophthalmology, Graduate School of Medicine, Nagoya University, Nagoya 464-8601, Japan.
(7)Dorn Research Institute, Columbia Veterans Affairs Health Care System, Columbia, SC 29209.
(8)Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208.
(9)Department of Ophthalmology, Graduate School of Medical Sciences, Nagoya City University, Nagoya 467-8601, Japan.
(10)Departamento de Oftalmologia e Ciências Visuais, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04023-062, Brazil.
(11)Department of Computer Science, University of Kentucky, Lexington, KY 40536.
(12)Doheny Eye Institute, Los Angeles, CA 90033.
(13)Department of Ophthalmology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
(14)Center for Digital Image Evaluation, Charlottesville, VA 22901.
(15)Department of Otolaryngology-Head and Neck Surgery, University Hospital of Lausanne, 1011 Lausanne, Switzerland.
(16)Department of Medical Biotechnology, Paul Ehrlich Institute, 63225 Langen, Germany.
(17)The Lieber Institute for Brain Development, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.
(18)Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037.
(19)Center for Targeted Drug Delivery, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, CA 92618.
(20)Organometallic and Organometalloid Chemistry Department, National Research Centre, Giza 12622, Egypt.
(21)Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY 40536.
(22)Department of Epidemiology and Biostatistics, University of South Carolina, Columbia, SC 29208.
(23)Center for Medication Safety and Efficacy, College of Pharmacy, University of South Carolina, Columbia, SC 29208.
(24)Department of Ophthalmology, University of Southern California Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
(25)Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
(26)Medtronic, Inc., Minneapolis, MN 55432.
(27)Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455.
(28)Department of Medical Statistics, University Medical Center Göttingen, D-37073 Göttingen, Germany.
(29)Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(30)Department of Pathology, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(31)Department of Orthopaedic Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(32)Department of Biomedical Engineering, School of Medicine, University of Virginia, Charlottesville, VA 22908.
(33)Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037; [Email] [Email]
(34)Center for Advanced Vision Science, School of Medicine, University of Virginia, Charlottesville, VA 22908; [Email] [Email]
(35)Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908.

Abstract

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.