DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

• Type of Material: Article
• Authors: Hiroki Kaneko, University of Kentucky; Sami Dridi, University of Kentucky; Valeria Tarallo, University of Kentucky; Bradley D. Gelfand, University of Kentucky; Benjamin J. Fowler, University of Kentucky; Won Gil Cho, University of Kentucky; Mark E. Kleinman, University of Kentucky; Steven L. Ponicsan, University of Colorado; William W. Hauswirth, University of Florida; Vince A. Chiodo, University of Florida; Katalin Karikó, University of Pennsylvania; Jae Wook Yoo, Sungkyunkwan University; Dong-Ki Lee, Sungkyunkwan University; Majda Hadziahmetovic, University of Pennsylvania; Ying Song, University of Pennsylvania; Smita Misra, Meharry Medical College; Gautam Chaudhuri, Meharry Medical College; Frank W. Buaas, Jackson Laboratory; Robert E. Braun, Jackson Laboratory; David R. Hinton, University of Southern California; Qing Zhang, Emory University; Hans Grossniklaus, Emory University; Jan M. Provis, Australian National University; Michele C. Madigan, University of New South Wales; Ann H. Milam, University of Pennsylvania; Nikki L. Justice, University of Kentucky; Romulo J.C. Albuquerque, University of Kentucky; Alexander D. Blandford, University of Kentucky; Sasha Bogdanovich, University of Kentucky; Yoshio Hirano, University of Kentucky; Jassir Witta, University of Kentucky; Elaine Fuchs, Rockefeller University; Dan R. Littman, New York University; Balmurali K. Ambati, University of Utah; Charles M. Rudin, Johns Hopkins University; Mark M.W. Chong, New York University; Patrick Provost, Laval University; Jennifer F. Kugel, University of Colorado; James A. Goodrich, University of Colorado; Joshua L. Dunaief, University of Pennsylvania; Judit Z. Baffi, University of Kentucky; Jayakrishna Ambati, University of Kentucky
• Language: English
• Date: 2011-03-17
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Macmillan Publishers Limited. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature09830
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 471
• Issue: 7338
• Start Page: 325
• End Page: +
• Grant/Funding Information: B.K.A. was supported by NEI/NIH grants, the VA Merit Award and the Department of Defense.; M.E.K. and S.B. were supported by NIH T32 grants.; J.A. was supported by National Eye Institute (NEI)/National Institutes of Health (NIH) grants, the Doris Duke Distinguished Clinical Scientist Award, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, the Dr. E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair, the Senior Scientist Investigator Award (Research to Prevent Blindness, RPB), and a departmental unrestricted grant from the RPB.; P.P. is a Senior Scholar from the Fonds de la Recherche en Santé du Québec (FRSQ).; DKL acknowledges support from Global Research Laboratory program by MEST, Korea.; J.Z.B. was supported by the University of Kentucky Physician Scientist Award, the International Retinal Research Foundation, and the American Health Assistance Foundation.
• Keywords: MOUSE OOCYTES; ARGONAUTE2; EXPRESSION; EMBRYONIC STEM-CELLS; LDL RECEPTOR; DIFFERENTIATION; RECOMBINATION; Multidisciplinary Sciences; CANCER; SIRNAS; MICRORNA BIOGENESIS
• Research Categories: Health Sciences, Opthamology; Health Sciences, Pathology

Abstract

Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.