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

被引：475

作者：

Kaneko, Hiroki ^{[1
]}

Dridi, Sami ^{[1
]}

Tarallo, Valeria ^{[1
]}

Gelfand, Bradley D. ^{[1
]}

Fowler, Benjamin J. ^{[1
]}

Cho, Won Gil ^{[1
,2
]}

Kleinman, Mark E. ^{[1
]}

Ponicsan, Steven L. ^{[3
]}

Hauswirth, William W. ^{[4
]}

Chiodo, Vince A. ^{[4
]}

Kariko, Katalin ^{[5
]}

Yoo, Jae Wook ^{[6
,7
,28
]}

Lee, Dong-ki ^{[6
,7
,28
]}

Hadziahmetovic, Majda ^{[8
]}

Song, Ying ^{[8
]}

Misra, Smita ^{[9
]}

Chaudhuri, Gautam ^{[9
]}

Buaas, Frank W. ^{[10
]}

Braun, Robert E. ^{[10
]}

Hinton, David R. ^{[11
]}

Zhang, Qing ^{[12
,13
]}

Grossniklaus, Hans E. ^{[12
,13
]}

Provis, Jan M. ^{[14
,15
]}

Madigan, Michele C. ^{[16
,17
]}

Milam, Ann H. ^{[8
]}

Justice, Nikki L. ^{[1
]}

Albuquerque, Romulo J. C. ^{[1
]}

Blandford, Alexander D. ^{[1
]}

Bogdanovich, Sasha ^{[1
]}

Hirano, Yoshio ^{[1
]}

Witta, Jassir ^{[18
]}

Fuchs, Elaine ^{[19
]}

Littman, Dan R. ^{[20
]}

Ambati, Balamurali K. ^{[21
,22
]}

Rudin, Charles M. ^{[23
]}

Chong, Mark M. W. ^{[20
,24
]}

Provost, Patrick ^{[25
,26
]}

Kugel, Jennifer F. ^{[3
]}

Goodrich, James A. ^{[3
]}

Dunaief, Joshua L. ^{[8
]}

Baffi, Judit Z. ^{[1
]}

Ambati, Jayakrishna ^{[1
,27
]}

机构：

[1] Univ Kentucky, Dept Ophthalmol & Visual Sci, Lexington, KY 40506 USA

[2] Yonsei Univ, Wonju Coll Med, Dept Anat, Wonju 220701, South Korea

[3] Univ Colorado, Dept Chem & Biochem, Boulder, CO 80309 USA

[4] Univ Florida, Dept Ophthalmol, Gainesville, FL 32610 USA

[5] Univ Penn, Sch Med, Dept Neurosurg, Philadelphia, PA 19104 USA

[6] Sungkyunkwan Univ, Sch Chem Mat Sci BK21, Suwon 440746, South Korea

[7] Sungkyunkwan Univ, Dept Chem, Suwon 440746, South Korea

[8] Univ Penn, Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[9] Meharry Med Coll, Dept Microbiol & Immunol, Nashville, TN 37208 USA

[10] Jackson Lab, Bar Harbor, ME 04609 USA

[11] Univ So Calif, Doheny Eye Inst, Arnold & Mabel Beckman Macular Res Ctr, Los Angeles, CA 90033 USA

[12] Emory Univ, Dept Ophthalmol, Atlanta, GA 30322 USA

[13] Emory Univ, Atlanta, GA 30322 USA

[14] Australian Natl Univ, ANU Med Sch, ARC Ctr Excellence Vis Sci, Canberra, ACT 0200, Australia

[15] Australian Natl Univ, Res Sch Biol, Canberra, ACT 0200, Australia

[16] Univ New S Wales, Sch Optometry & Vis Sci, Kensington, NSW 2033, Australia

[17] Univ Sydney, Save Sight Inst, Sydney, NSW 2001, Australia

[18] Univ Kentucky, Dept Internal Med, Lexington, KY 40506 USA

[19] Rockefeller Univ, Howard Hughes Med Inst, Lab Mammalian Cell Biol & Dev, New York, NY 10065 USA

[20] NYU, Sch Med, Howard Hughes Med Inst, Kimmel Ctr Biol & Med,Skirball Inst, New York, NY 10016 USA

[21] Univ Utah, Sch Med, Moran Eye Ctr, Dept Ophthalmol & Visual Sci, Salt Lake City, UT 84132 USA

[22] Vet Affairs Salt Lake City Healthcare Syst, Dept Ophthalmol, Salt Lake City, UT 84148 USA

[23] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Dept Oncol, Baltimore, MD 21231 USA

[24] Walter & Eliza Hall Inst Med Res, Autoimmun & Transplantat Div, Parkville, Vic 3052, Australia

[25] Univ Laval, CHUL Res Ctr CHUQ, Quebec City, PQ G1K 7P4, Canada

[26] Univ Laval, Fac Med, Quebec City, PQ G1K 7P4, Canada

[27] Univ Kentucky, Dept Physiol, Lexington, KY 40506 USA

[28] Sungkyunkwan Univ, Global Res Lab RNAi Med, Suwon 440746, South Korea

来源：

NATURE | 2011年 / 471卷 / 7338期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

EMBRYONIC STEM-CELLS; MICRORNA BIOGENESIS; MOUSE OOCYTES; LDL RECEPTOR; RECOMBINATION; ARGONAUTE2; EXPRESSION; CANCER; SIRNAS; DIFFERENTIATION;

D O I：

10.1038/nature09830

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：325 / +

页数：8

共 52 条

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Alexander JJ, 2008, ADV EXP MED BIOL, V613, P121, DOI 10.1007/978-0-387-74904-4_13

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