Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature volume 471, pages 325–330 (2011)Cite this article

This article has been updated

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: DICER1 deficit in GA induces RPE degeneration.
Figure 2: Alu RNA accumulation in GA triggered by DICER reduction.
Figure 3: DICER1 degrades Alu RNA.
Figure 4: DICER1 protects RPE cells from Alu RNA cytotoxicity.
Figure 5: DICER1 dysregulation induces RPE cell death via Alu RNA accumulation.

Similar content being viewed by others

Accession codes

Data deposits

The Alu sequences have been deposited in GenBank under the accession numbers HN176584 and HN176585.

Change history

  • 16 March 2011

    In the paragraph beginning, ‘Subretinal injection delivered Alu RNA to RPE cells...’, two figure citations were corrected.

References

  1. Kleinman, M. E. et al. Sequence- and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591–597 (2008)

    Article  CAS  ADS  Google Scholar 

  2. Takeda, A. et al. CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 460, 225–230 (2009)

    Article  CAS  ADS  Google Scholar 

  3. Ferrara, N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nature Med. 16, 1107–1111 (2010)

    Article  CAS  Google Scholar 

  4. Ambati, J., Ambati, B. K., Yoo, S. H., Ianchulev, S. & Adamis, A. P. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv. Ophthalmol. 48, 257–293 (2003)

    Article  Google Scholar 

  5. Bernstein, E., Caudy, A. A., Hammond, S. M. & Hannon, G. J. Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409, 363–366 (2001)

    Article  CAS  ADS  Google Scholar 

  6. Batzer, M. A. & Deininger, P. L. Alu repeats and human genomic diversity. Nature Rev. Genet. 3, 370–379 (2002)

    Article  CAS  Google Scholar 

  7. Gregory, R. I. et al. The Microprocessor complex mediates the genesis of microRNAs. Nature 432, 235–240 (2004)

    Article  CAS  ADS  Google Scholar 

  8. Liu, J. et al. Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004)

    Article  CAS  ADS  Google Scholar 

  9. Meister, G. et al. Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs. Mol. Cell 15, 185–197 (2004)

    Article  CAS  Google Scholar 

  10. Harfe, B. D., McManus, M. T., Mansfield, J. H., Hornstein, E. & Tabin, C. J. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc. Natl Acad. Sci. USA 102, 10898–10903 (2005)

    Article  CAS  ADS  Google Scholar 

  11. Iacovelli, J. et al. Generation of cre transgenic mice with postnatal RPE-specific ocular expression. Invest. Ophthalmol. Vis. Sci. 10.1167/iovs.10–6347 (6 January 2011)

  12. Alexander, J. J. & Hauswirth, W. W. Adeno-associated viral vectors and the retina. Adv. Exp. Med. Biol. 613, 121–128 (2008)

    Article  CAS  Google Scholar 

  13. Chong, M. M., Rasmussen, J. P., Rudensky, A. Y. & Littman, D. R. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 2005–2017 (2008)

    Article  CAS  Google Scholar 

  14. Yi, R. et al. DGCR8-dependent microRNA biogenesis is essential for skin development. Proc. Natl Acad. Sci. USA 106, 498–502 (2009)

    Article  CAS  ADS  Google Scholar 

  15. O’Carroll, D. et al. A Slicer-independent role for Argonaute 2 in hematopoiesis and the microRNA pathway. Genes Dev. 21, 1999–2004 (2007)

    Article  Google Scholar 

  16. Chong, M. M. et al. Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev. 24, 1951–1960 (2010)

    Article  CAS  Google Scholar 

  17. Babiarz, J. E., Ruby, J. G., Wang, Y., Bartel, D. P. & Blelloch, R. Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. Genes Dev. 22, 2773–2785 (2008)

    Article  CAS  Google Scholar 

  18. Schaefer, A. et al. Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction. J. Exp. Med. 207, 1843–1851 (2010)

    Article  CAS  Google Scholar 

  19. Diederichs, S. & Haber, D. A. Dual role for Argonautes in microRNA processing and posttranscriptional regulation of microRNA expression. Cell 131, 1097–1108 (2007)

    Article  CAS  Google Scholar 

  20. Kaneda, M., Tang, F., O’Carroll, D., Lao, K. & Surani, M. A. Essential role for Argonaute2 protein in mouse oogenesis. Epigenetics Chromatin 2, 9 (2009)

    Article  Google Scholar 

  21. Su, H., Trombly, M. I., Chen, J. & Wang, X. Essential and overlapping functions for mammalian Argonautes in microRNA silencing. Genes Dev. 23, 304–317 (2009)

    Article  CAS  Google Scholar 

  22. Chendrimada, T. P. et al. TRBP recruits the Dicer complex to Ago2 for microRNA processing and gene silencing. Nature 436, 740–744 (2005)

    Article  CAS  ADS  Google Scholar 

  23. Cummins, J. M. et al. The colorectal microRNAome. Proc. Natl Acad. Sci. USA 103, 3687–3692 (2006)

    Article  CAS  ADS  Google Scholar 

  24. Schonborn, J. et al. Monoclonal antibodies to double-stranded RNA as probes of RNA structure in crude nucleic acid extracts. Nucleic Acids Res. 19, 2993–3000 (1991)

    Article  CAS  Google Scholar 

  25. Kato, H. et al. Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J. Exp. Med. 205, 1601–1610 (2008)

    Article  CAS  Google Scholar 

  26. Saleh, M. C. et al. The endocytic pathway mediates cell entry of dsRNA to induce RNAi silencing. Nature Cell Biol. 8, 793–802 (2006)

    Article  CAS  Google Scholar 

  27. Yang, Z. et al. Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N. Engl. J. Med. 359, 1456–1463 (2008)

    Article  CAS  Google Scholar 

  28. Dunaief, J. L., Dentchev, T., Ying, G. S. & Milam, A. H. The role of apoptosis in age-related macular degeneration. Arch. Ophthalmol. 120, 1435–1442 (2002)

    Article  Google Scholar 

  29. Davis, T. H. et al. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J. Neurosci. 28, 4322–4330 (2008)

    Article  CAS  Google Scholar 

  30. Damiani, D. et al. Dicer inactivation leads to progressive functional and structural degeneration of the mouse retina. J. Neurosci. 28, 4878–4887 (2008)

    Article  CAS  Google Scholar 

  31. Chen, J. F. et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc. Natl Acad. Sci. USA 105, 2111–2116 (2008)

    Article  CAS  ADS  Google Scholar 

  32. Merritt, W. M. et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N. Engl. J. Med. 359, 2641–2650 (2008)

    Article  CAS  Google Scholar 

  33. Kumar, M. S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev. 23, 2700–2704 (2009)

    Article  CAS  Google Scholar 

  34. Hill, D. A. et al. DICER1 mutations in familial pleuropulmonary blastoma. Science 325, 965 (2009)

    Article  CAS  ADS  Google Scholar 

  35. Nicholls, R. D., Fischel-Ghodsian, N. & Higgs, D. R. Recombination at the human α-globin gene cluster: sequence features and topological constraints. Cell 49, 369–378 (1987)

    Article  CAS  Google Scholar 

  36. Nyström-Lahti, M. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer. Nature Med. 1, 1203–1206 (1995)

    Article  Google Scholar 

  37. Lehrman, M. A. et al. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227, 140–146 (1985)

    Article  CAS  ADS  Google Scholar 

  38. Lehrman, M. A., Goldstein, J. L., Russell, D. W. & Brown, M. S. Duplication of seven exons in LDL receptor gene caused by Alu-Alu recombination in a subject with familial hypercholesterolemia. Cell 48, 827–835 (1987)

    Article  CAS  Google Scholar 

  39. Wallace, M. R. et al. A de novo Alu insertion results in neurofibromatosis type 1. Nature 353, 864–866 (1991)

    Article  CAS  ADS  Google Scholar 

  40. Volpe, T. A. et al. Regulation of heterochromatic silencing and histone H3 lysine-9 methylation by RNAi. Science 297, 1833–1837 (2002)

    Article  CAS  ADS  Google Scholar 

  41. Hall, I. M. et al. Establishment and maintenance of a heterochromatin domain. Science 297, 2232–2237 (2002)

    Article  CAS  ADS  Google Scholar 

  42. Prades, C., Laurent, A. M., Puechberty, J., Yurov, Y. & Roizes, G. SINE and LINE within human centromeres. J. Mol. Evol. 42, 37–43 (1996)

    Article  CAS  ADS  Google Scholar 

  43. Saito, Y. et al. Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512–5p with downregulation of Mcl-1 in human gastric cancer cells. Oncogene 28, 2738–2744 (2009)

    Article  CAS  Google Scholar 

  44. Murchison, E. P., Partridge, J. F., Tam, O. H., Cheloufi, S. & Hannon, G. J. Characterization of Dicer-deficient murine embryonic stem cells. Proc. Natl Acad. Sci. USA 102, 12135–12140 (2005)

    Article  CAS  ADS  Google Scholar 

  45. Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005)

    Article  CAS  Google Scholar 

  46. Tam, O. H. et al. Pseudogene-derived small interfering RNAs regulate gene expression in mouse oocytes. Nature 453, 534–538 (2008)

    Article  CAS  ADS  Google Scholar 

  47. Watanabe, T. et al. Endogenous siRNAs from naturally formed dsRNAs regulate transcripts in mouse oocytes. Nature 453, 539–543 (2008)

    Article  CAS  ADS  Google Scholar 

  48. Nakagawa, A., Shi, Y., Kage-Nakadai, E., Mitani, S. & Xue, D. Caspase-dependent conversion of Dicer ribonuclease into a death-promoting deoxyribonuclease. Science 328, 327–334 (2010)

    Article  CAS  ADS  Google Scholar 

  49. Kohany, O., Gentles, A. J., Hankus, L. & Jurka, J. Annotation, submission and screening of repetitive elements in Repbase: RepbaseSubmitter and Censor. BMC Bioinformatics 7, 474 (2006)

    Article  Google Scholar 

  50. Yang, P., Tyrrell, J., Han, I. & Jaffe, G. J. Expression and modulation of RPE cell membrane complement regulatory proteins. Invest. Ophthalmol. Vis. Sci. 50, 3473–3481 (2009)

    Article  Google Scholar 

  51. Shaikh, T. H., Roy, A. M., Kim, J., Batzer, M. A. & Deininger, P. L. cDNAs derived from primary and small cytoplasmic Alu (scAlu) transcripts. J. Mol. Biol. 271, 222–234 (1997)

    Article  CAS  Google Scholar 

  52. Allen, T. A., Von Kaenel, S., Goodrich, J. A. & Kugel, J. F. The SINE-encoded mouse B2 RNA represses mRNA transcription in response to heat shock. Nature Struct. Mol. Biol. 11, 816–821 (2004)

    Article  CAS  Google Scholar 

Download references

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 Santé du Québec (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.

Author information

Author notes

  1. Hiroki Kaneko, Sami Dridi and Valeria Tarallo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, 40506, Kentucky, USA

    Hiroki Kaneko, Sami Dridi, Valeria Tarallo, Bradley D. Gelfand, Benjamin J. Fowler, Won Gil Cho, Mark E. Kleinman, Nikki L. Justice, Romulo J. C. Albuquerque, Alexander D. Blandford, Sasha Bogdanovich, Yoshio Hirano, Judit Z. Baffi & Jayakrishna Ambati

  2. Department of Anatomy, Yonsei University Wonju College of Medicine, Wonju City 220-701, Korea

    Won Gil Cho

  3. Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, 80309, Colorado, USA

    Steven L. Ponicsan, Jennifer F. Kugel & James A. Goodrich

  4. Department of Ophthalmology, University of Florida, Gainesville, 32610, Florida, USA

    William W. Hauswirth & Vince A. Chiodo

  5. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Katalin Karikó

  6. Global Research Laboratory for RNAi Medicine & BK21 School of Chemical Materials Science and Department of Chemistry, Sungkyunkwan University, Suwon 440-746, Korea

    Jae Wook Yoo & Dong-ki Lee

  7. F.M. Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Majda Hadziahmetovic, Ying Song, Ann H. Milam & Joshua L. Dunaief

  8. Department of Microbiology and Immunology, Meharry Medical College, Nashville, 37208, Tennessee, USA

    Smita Misra & Gautam Chaudhuri

  9. The Jackson Laboratory, Bar Harbor, 04609, Maine, USA

    Frank W. Buaas & Robert E. Braun

  10. The Arnold and Mabel Beckman Macular Research Center at the Doheny Eye Institute, University of Southern California, Los Angeles, 90033, California, USA

    David R. Hinton

  11. Departments of Ophthalmology & Pathology, Emory University Atlanta, Georgia, 30322, USA

    Qing Zhang & Hans E. Grossniklaus

  12. ARC Centre of Excellence in Vision Science, ANU Medical School and Research School of Biology, The Australian National University, Canberra, 0200, Australian Capital Territory, Australia

    Jan M. Provis

  13. School of Optometry and Vision Science, The University of New South Wales, Kensington, 2033, New South Wales, Australia

    Michele C. Madigan

  14. Save Sight Institute, The University of Sydney, Sydney, 2001, New South Wales, Australia

    Michele C. Madigan

  15. Department of Internal Medicine, University of Kentucky, Lexington, 40506, Kentucky, USA

    Jassir Witta

  16. Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, 10065, New York, USA

    Elaine Fuchs

  17. Howard Hughes Medical Institute, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, 10016, New York, USA

    Dan R. Littman & Mark M. W. Chong

  18. Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, 84132, Utah, USA

    Balamurali K. Ambati

  19. Department of Ophthalmology, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, 84148, Utah, USA

    Balamurali K. Ambati

  20. Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Johns Hopkins University, Baltimore, 21231, Maryland, USA

    Charles M. Rudin

  21. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute, Parkville, 3052, Victoria, Australia

    Mark M. W. Chong

  22. CHUL Research Center/CHUQ and Faculty of Medicine, Université Laval, Quebec, Quebec G1K 7P4, Canada

    Patrick Provost

  23. Department of Physiology, University of Kentucky, Lexington, 40506, Kentucky, USA

    Jayakrishna Ambati

Authors
  1. Hiroki Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sami Dridi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valeria Tarallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bradley D. Gelfand
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin J. Fowler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Won Gil Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mark E. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Steven L. Ponicsan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. William W. Hauswirth
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Vince A. Chiodo
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katalin Karikó
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jae Wook Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Dong-ki Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Majda Hadziahmetovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Ying Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Smita Misra
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Gautam Chaudhuri
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Frank W. Buaas
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Robert E. Braun
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. David R. Hinton
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Qing Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Hans E. Grossniklaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Jan M. Provis
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Michele C. Madigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Ann H. Milam
    View author publications

    You can also search for this author in PubMed Google Scholar

  26. Nikki L. Justice
    View author publications

    You can also search for this author in PubMed Google Scholar

  27. Romulo J. C. Albuquerque
    View author publications

    You can also search for this author in PubMed Google Scholar

  28. Alexander D. Blandford
    View author publications

    You can also search for this author in PubMed Google Scholar

  29. Sasha Bogdanovich
    View author publications

    You can also search for this author in PubMed Google Scholar

  30. Yoshio Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  31. Jassir Witta
    View author publications

    You can also search for this author in PubMed Google Scholar

  32. Elaine Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  33. Dan R. Littman
    View author publications

    You can also search for this author in PubMed Google Scholar

  34. Balamurali K. Ambati
    View author publications

    You can also search for this author in PubMed Google Scholar

  35. Charles M. Rudin
    View author publications

    You can also search for this author in PubMed Google Scholar

  36. Mark M. W. Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  37. Patrick Provost
    View author publications

    You can also search for this author in PubMed Google Scholar

  38. Jennifer F. Kugel
    View author publications

    You can also search for this author in PubMed Google Scholar

  39. James A. Goodrich
    View author publications

    You can also search for this author in PubMed Google Scholar

  40. Joshua L. Dunaief
    View author publications

    You can also search for this author in PubMed Google Scholar

  41. Judit Z. Baffi
    View author publications

    You can also search for this author in PubMed Google Scholar

  42. Jayakrishna Ambati
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

H.K., S.D., V.T., W.G.C., B.J.F., M.E.K., S.L.P., J.F.K., J.A.G., K.K., N.L.J., B.D.G., Y.H., R.J.C.A., A.D.B., S.B, J.W., M.H, Y.S. and J.Z.B. performed experiments. W.W.H., V.A.C, D.-k.L., J.W.Y., C.M.R, D.R.H., H.E.G., Q.Z., J.M.P., M.C.M., A.H.M., M.M.W.C., D.R.L., E.F., P.P., F.W.B., R.E.B., S.M., G.C. and J.L.D. provided tissues or reagents. J.A. conceived and directed the project, and wrote the paper with assistance from P.P., C.M.R., K.K., J.F.K., J.A.G., E.F., M.M.W.C., B.J.F., B.D.G. and B.K.A. All authors had the opportunity to discuss the results and comment on the manuscript.

Corresponding author

Correspondence to Jayakrishna Ambati.

Ethics declarations

Competing interests

J.A. is named as an inventor on patent applications filed by his employer, the University of Kentucky, on technologies described in this paper. W.W.H. and the University of Florida have a financial interest in the use of AAV therapies, and own equity in a company (AGTC Inc.) that might, in the future, commercialize some aspects of this work.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-26 with legends, Supplementary Notes, supplementary Materials and Methods and additional references. (PDF 2605 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaneko, H., Dridi, S., Tarallo, V. et al. DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature 471, 325–330 (2011). https://doi.org/10.1038/nature09830

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature09830

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing