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; Jayakrishna Ambati

doi:10.1038/nature09830

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. HintonQing 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, Jayakrishna Ambati^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

533 Citations (Scopus)

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.

Original language	English
Pages (from-to)	325-332
Number of pages	8
Journal	Nature
Volume	471
Issue number	7338
DOIs	https://doi.org/10.1038/nature09830
Publication status	Published - 17 Mar 2011

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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., ... Ambati, J. (2011). DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration. Nature, 471(7338), 325-332. https://doi.org/10.1038/nature09830

@article{49baa71e6ff041238fc895cb2e13464b,

title = "DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration",

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.",

author = "Hiroki Kaneko and Sami Dridi and Valeria Tarallo and Gelfand, {Bradley D.} and Fowler, {Benjamin J.} and Cho, {Won Gil} and Kleinman, {Mark E.} and Ponicsan, {Steven L.} and Hauswirth, {William W.} and Chiodo, {Vince A.} and Katalin Karik{\'o} and Yoo, {Jae Wook} and Lee, {Dong Ki} and Majda Hadziahmetovic and Ying Song and Smita Misra and Gautam Chaudhuri and Buaas, {Frank W.} and Braun, {Robert E.} and Hinton, {David R.} and Qing Zhang and Grossniklaus, {Hans E.} and Provis, {Jan M.} and Madigan, {Michele C.} and Milam, {Ann H.} and Justice, {Nikki L.} and Albuquerque, {Romulo J.C.} and Blandford, {Alexander D.} and Sasha Bogdanovich and Yoshio Hirano and Jassir Witta and Elaine Fuchs and Littman, {Dan R.} and Ambati, {Balamurali K.} and Rudin, {Charles M.} and Chong, {Mark M.W.} and Patrick Provost and Kugel, {Jennifer F.} and Goodrich, {James A.} and Dunaief, {Joshua L.} and Baffi, {Judit Z.} and Jayakrishna Ambati",

year = "2011",

month = mar,

day = "17",

doi = "10.1038/nature09830",

language = "English",

volume = "471",

pages = "325--332",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7338",

}

Kaneko, H, Dridi, S, Tarallo, V, Gelfand, BD, Fowler, BJ, Cho, WG, Kleinman, ME, Ponicsan, SL, Hauswirth, WW, Chiodo, VA, Karikó, K, Yoo, JW, Lee, DK, Hadziahmetovic, M, Song, Y, Misra, S, Chaudhuri, G, Buaas, FW, Braun, RE, Hinton, DR, Zhang, Q, Grossniklaus, HE, Provis, JM, Madigan, MC, Milam, AH, Justice, NL, Albuquerque, RJC, Blandford, AD, Bogdanovich, S, Hirano, Y, Witta, J, Fuchs, E, Littman, DR, Ambati, BK, Rudin, CM, Chong, MMW, Provost, P, Kugel, JF, Goodrich, JA, Dunaief, JL, Baffi, JZ & Ambati, J 2011, 'DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration', Nature, vol. 471, no. 7338, pp. 325-332. https://doi.org/10.1038/nature09830

TY - JOUR

T1 - DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

AU - Kaneko, Hiroki

AU - Dridi, Sami

AU - Tarallo, Valeria

AU - Gelfand, Bradley D.

AU - Fowler, Benjamin J.

AU - Cho, Won Gil

AU - Kleinman, Mark E.

AU - Ponicsan, Steven L.

AU - Hauswirth, William W.

AU - Chiodo, Vince A.

AU - Karikó, Katalin

AU - Yoo, Jae Wook

AU - Lee, Dong Ki

AU - Hadziahmetovic, Majda

AU - Song, Ying

AU - Misra, Smita

AU - Chaudhuri, Gautam

AU - Buaas, Frank W.

AU - Braun, Robert E.

AU - Hinton, David R.

AU - Zhang, Qing

AU - Grossniklaus, Hans E.

AU - Provis, Jan M.

AU - Madigan, Michele C.

AU - Milam, Ann H.

AU - Justice, Nikki L.

AU - Albuquerque, Romulo J.C.

AU - Blandford, Alexander D.

AU - Bogdanovich, Sasha

AU - Hirano, Yoshio

AU - Witta, Jassir

AU - Fuchs, Elaine

AU - Littman, Dan R.

AU - Ambati, Balamurali K.

AU - Rudin, Charles M.

AU - Chong, Mark M.W.

AU - Provost, Patrick

AU - Kugel, Jennifer F.

AU - Goodrich, James A.

AU - Dunaief, Joshua L.

AU - Baffi, Judit Z.

AU - Ambati, Jayakrishna

PY - 2011/3/17

Y1 - 2011/3/17

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=79952786337&partnerID=8YFLogxK

U2 - 10.1038/nature09830

DO - 10.1038/nature09830

M3 - Article

SN - 0028-0836

VL - 471

SP - 325

EP - 332

JO - Nature

JF - Nature

IS - 7338

ER -

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

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