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

Hiroki Kaneko, Sami Dridi, Valeria Tarallo, Bradley D. Gelfand, Benjamin J. Fowler, Won Gil Cho, Mark E. Kleinman, Steven L. Ponicsan, William W. Hauswirth, Vince A. Chiodo, Katalin Karikó, Jae Wook Yoo, Dong-ki Lee, Majda Hadziahmetovic, Ying Song, Smita Misra, Gautam Chaudhuri, Frank W. Buaas, Robert E. Braun, David R. Hinton, Qing Zhang, Hans E. Grossniklaus, Jan M. Provis, Michele C. Madigan, Ann H. Milam, Nikki L. Justice, Romulo J. C. Albuquerque, Alexander D. Blandford, Sasha Bogdanovich, Yoshio Hirano, Jassir Witta, Elaine Fuchs, Dan R. Littman, Balamurali K. Ambati, Charles M. Rudin, Mark M. W. Chong, Patrick Provost, Jennifer F. Kugel, James A. Goodrich, Joshua L. Dunaief, Judit Z. Baffi and Jayakrishna Ambati ()
Additional contact information
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 at Boulder
William W. Hauswirth: University of Florida
Vince A. Chiodo: University of Florida
Katalin Karikó: University of Pennsylvania School of Medicine
Jae Wook Yoo: Sungkyunkwan University
Dong-ki Lee: Sungkyunkwan University
Majda Hadziahmetovic: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania
Ying Song: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania
Smita Misra: Meharry Medical College
Gautam Chaudhuri: Meharry Medical College
Frank W. Buaas: The Jackson Laboratory
Robert E. Braun: The Jackson Laboratory
David R. Hinton: The Arnold and Mabel Beckman Macular Research Center at the Doheny Eye Institute, University of Southern California
Qing Zhang: Emory University Atlanta
Hans E. Grossniklaus: Emory University Atlanta
Jan M. Provis: ARC Centre of Excellence in Vision Science, ANU Medical School and Research School of Biology, The Australian National University
Michele C. Madigan: School of Optometry and Vision Science, The University of New South Wales
Ann H. Milam: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, 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: Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University
Dan R. Littman: Howard Hughes Medical Institute, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Balamurali K. Ambati: Moran Eye Center, University of Utah School of Medicine
Charles M. Rudin: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University
Mark M. W. Chong: Howard Hughes Medical Institute, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine
Patrick Provost: CHUL Research Center/CHUQ and Faculty of Medicine, Université Laval
Jennifer F. Kugel: University of Colorado at Boulder
James A. Goodrich: University of Colorado at Boulder
Joshua L. Dunaief: F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania
Judit Z. Baffi: University of Kentucky
Jayakrishna Ambati: University of Kentucky

Nature, 2011, vol. 471, issue 7338, 325-330

Abstract: 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.

Date: 2011
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DOI: 10.1038/nature09830

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