DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration
Open accessAbstract
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.
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The RPE of patients with geographic atrophy have reduced miRNA processing enzyme DICER1, and the ablation of this specific gene is sufficient to induce RPE degeneration in mice.
“A hint for a potential mechanistic involvement of MAPKs in AMD comes from the finding that the RPE of patients with geographic atrophy, an untreatable advanced form of dry (non-neovascular) AMD, have reduced miRNA processing enzyme DICER1, and the ablation of this specific gene is sufficient to induce RPE degeneration in mice [ 33 ]”
From MAPK Pathways in Ocular Pathophysiology: Potential Therapeutic Drugs and Challenges (2023) · cites this paper as [33]
In geographic atrophy (GA), the miRNA-processing enzyme DICER1 is reduced in retinal pigmented epithelium (RPE) cells, causing an accumulation of Alu RNA.
“It has been shown that in a form of age-related macular degeneration, known as geographic atrophy (GA), the miRNA-processing enzyme, DICER1, is reduced in retinal pigmented epithelium (RPE) cells, causing an accumulation of Alu RNA (Kaneko et al., 2011).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Kaneko et al., 2011
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“A hint for a potential mechanistic involvement of MAPKs in AMD comes from the finding that the RPE of patients with geographic atrophy, an untreatable advanced form of dry (non-neovascular) AMD, have reduced miRNA processing enzyme DICER1, and the ablation of this specific gene is sufficient to induce RPE degeneration…”
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The learning curve of murine subretinal injection among clinically trained ophthalmic surgeons
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- Authors
- Kaneko, H., Dridi, S., Tarallo, V., Gelfand, B. D., Fowler, B. J., Cho, W. G., Kleinman, M. E., Ponicsan, S. L., Hauswirth, W. W., Chiodo, V. A., Karikó, K., Yoo, J. W., Lee, D.-K., Hadziahmetovic, M., Song, Y., Misra, S., Chaudhuri, G., Buaas, F. W., Braun, R. E., Hinton, D. R., Zhang, Q., Grossniklaus, H. E., Provis, J. M., Madigan, M. C., Milam, A. H., Justice, N. L., Albuquerque, R. J. C., Blandford, A. D., Bogdanovich, S., Hirano, Y., Witta, J., Fuchs, E., Littman, D. R., Ambati, B. K., Rudin, C. M., Chong, M. M. W., Provost, P., Kugel, J. F., Goodrich, J. A., Dunaief, J. L., Baffi, J. Z., & Ambati, J.
- Affiliations
- University of Kentucky (US)
- University of Colorado Boulder (US)
- University of Florida (US)
- University of Pennsylvania (US)
- Sungkyunkwan University (KR)
- Meharry Medical College (US)
- Jackson Laboratory (US)
- University of Southern California (US)
- Emory University (US)
- Australian National University (AU)
- The University of Sydney (AU)
- Howard Hughes Medical Institute (US)
- University of Utah (US)
- Johns Hopkins University (US)
- Centre hospitalier universitaire de Québec (CA)
- Corresponding author
- Ambati, Jayakrishna
- ORCID
- Kaneko, Hiroki
- Dridi, Sami
- Tarallo, Valeria
- Gelfand, Bradley D.
- Fowler, Benjamin J.
- Cho, Won Gil
- Kleinman, Mark E.
- Hauswirth, William W.
- Chiodo, Vince A.
- Karikó, Katalin
- Lee, Dong-ki
- Hadziahmetovic, Majda
- Song, Ying
- Misra, Smita
- Braun, Robert E.
- Hinton, David R.
- Zhang, Qing
- Grossniklaus, Hans E.
- Provis, Jan M.
- Madigan, Michele C.
- Bogdanovich, Sasha
- Hirano, Yoshio
- Fuchs, Elaine
- Littman, Dan R.
- Ambati, Balamurali K.
- Rudin, Charles M.
- Chong, Mark M. W.
- Provost, Patrick
- Kugel, Jennifer F.
- Goodrich, James A.
- Dunaief, Joshua L.
- Ambati, Jayakrishna
- Venue
- Nature
- Published
- 2011-02-06
- Volume
- 471
- Issue
- 7338
- Pages
- 325-330
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3077055
- OpenAlex
- W2085350682
- Cited by
- 601
- References
- 52
- Citations by year
- 2026: 11 · 2025: 17 · 2024: 37 · 2023: 21 · 2022: 32 · 2021: 42 · 2020: 36 · 2019: 37 · 2018: 37 · 2017: 40 · 2016: 37 · 2015: 50 · 2014: 53 · 2013: 52 · 2012: 70
- FWCI
- 60.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (T32HL091812)
- National Eye Institute (R01EY020672, P-30-EY06360, P30EY003040, R01EY017950, P30EY021721, R01EY018836, R01EY015422, R01EY001545, R01EY018350, R21EY019778, P30EY008571, NIHU10EY013729, RC1EY020442, R01EY017182, R01EY011123, P30EY006360, R01EY015240, P30EY014800)
- National Institute of General Medical Sciences (R01GM068414)
- National Institute of Allergy and Infectious Diseases (R21AI076757)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD027215)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Keywords
- DICER1, Alu RNA, geographic atrophy, age-related macular degeneration, microRNA processing, antisense oligonucleotides, blindness
- MeSH terms
- Animals, Cell Survival, Cells, Cultured, Humans, Macular Degeneration, Molecular Sequence Data, Phenotype, RNA, Oligonucleotides, Antisense, Cell Death, Alu Elements, MicroRNAs, Ribonuclease III, Mice, DEAD-box RNA Helicases, Retinal Pigment Epithelium, Gene Knockdown Techniques
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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