Journal article
DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration
H Kaneko, S Dridi, V Tarallo, BD Gelfand, BJ Fowler, WG Cho, ME Kleinman, SL Ponicsan, WW Hauswirth, VA Chiodo, K Karikó, JW Yoo, DK Lee, M Hadziahmetovic, Y Song, S Misra, G Chaudhuri, FW Buaas, RE Braun, DR Hinton Show all
Nature | NATURE PUBLISHING GROUP | Published : 2011
DOI: 10.1038/nature09830
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 dep..
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Grants
Awarded by Macula Vision Research Foundation
Funding Acknowledgements
We thank M. Chrenek, J. Garcia-Perez, T. Heidmann, C. Kanellopoulou, D. M. Livingston, J. V. Moran, R. F. Mullins, J. M. Nickerson, E. A. Pearce, A. Tarakhovsky, B. Vogelstein, V. E. Velculescu and D. J. Zack for providing mice, reagents or tissues; R. King, L. Xu, M. McConnell, C. Payne, G. R. Pattison, G. J. Jaffe, S. Medearis and C. Spee for technical assistance; and A. Sinai, R. Mohan, T. S. Khurana, R. A. Brekken, P. L. Deininger, S. Bondada, P. A. Pearson, A. M. Rao, G. S. Rao and K. Ambati for discussions. J. A. was supported by National Eye Institute (NEI)/National Institutes of Health (NIH) grants R01EY015422, R01EY018350, R01EY018836, R01EY020672, R21EY019778, RC1EY020442, the Doris Duke Distinguished Clinical Scientist Award, the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research, and the Dr E. Vernon Smith and Eloise C. Smith Macular Degeneration Endowed Chair. Research to Prevent Blindness Senior Scientist Investigator Awards or departmental unrestricted grants supported J. A., H. E. G. and W. W. H.; J. Z. B. was supported by University of Kentucky Physician Scientist Award, International Retinal Research Foundation, and American Health Assistance Foundation; B. K. A. by VA Merit Award and Department of Defense; D.-k. L. by Global Research Laboratory program by MEST, Korea; D. R. H. by Arnold and Mabel Beckman Foundation; W. W. H. by Macular Vision Research Foundation and Foundation Fighting Blindness; J. M. P. by ARC Centres of Excellence Grant CE0561903; M. C. M. by Sydney Foundation for Medical Research. B. K. A was supported by NIH R01EY017182 and R01EY017950; R. E. B. by NIH R01HD027215; G. C. by NIH R21AI076757; H. E. G. by NIH P30EY06360; W. W. H. by NIH U10EY013729, R01EY011123, and P30EY008571; J. F. K. and J. A. G. by NIH R01GM068414; J. L. D. by NIH R01EY015240; D. R. H. by NIH P30EY003040 and R01EY001545; M. E. K. and S. B. by NIH T32HL091812. P. P. is a Senior Scholar from the Fonds de la Recherche en Sante du Quebec (FRSQ). M. M. W. C. is a QEII Fellow of the Australian Research Council and is supported by National Health and Medical Research Council, Australia Project Grant 637228. E. F. and D. R. L. are investigators of the Howard Hughes Medical Institute.