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.
authors.affiliation: Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kaneko
authors.forename: Sami
authors.initials: S
authors.lastname: Dridi
authors.forename: Valeria
authors.initials: V
authors.lastname: Tarallo
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Gelfand
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Fowler
authors.forename: Won Gil
authors.initials: WG
authors.lastname: Cho
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kleinman
authors.forename: Steven L
authors.initials: SL
authors.lastname: Ponicsan
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Vince A
authors.initials: VA
authors.lastname: Chiodo
authors.forename: Katalin
authors.initials: K
authors.lastname: Karikó
authors.forename: Jae Wook
authors.initials: JW
authors.lastname: Yoo
authors.forename: Dong-ki
authors.initials: DK
authors.lastname: Lee
authors.forename: Majda
authors.initials: M
authors.lastname: Hadziahmetovic
authors.forename: Ying
authors.initials: Y
authors.lastname: Song
authors.forename: Smita
authors.initials: S
authors.lastname: Misra
authors.forename: Gautam
authors.initials: G
authors.lastname: Chaudhuri
authors.forename: Frank W
authors.initials: FW
authors.lastname: Buaas
authors.forename: Robert E
authors.initials: RE
authors.lastname: Braun
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.forename: Jan M
authors.initials: JM
authors.lastname: Provis
authors.forename: Michele C
authors.initials: MC
authors.lastname: Madigan
authors.forename: Ann H
authors.initials: AH
authors.lastname: Milam
authors.forename: Nikki L
authors.initials: NL
authors.lastname: Justice
authors.forename: Romulo J C
authors.initials: RJ
authors.lastname: Albuquerque
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Blandford
authors.forename: Sasha
authors.initials: S
authors.lastname: Bogdanovich
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirano
authors.forename: Jassir
authors.initials: J
authors.lastname: Witta
authors.forename: Elaine
authors.initials: E
authors.lastname: Fuchs
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Mark M W
authors.initials: MM
authors.lastname: Chong
authors.forename: Patrick
authors.initials: P
authors.lastname: Provost
authors.forename: Jennifer F
authors.initials: JF
authors.lastname: Kugel
authors.forename: James A
authors.initials: JA
authors.lastname: Goodrich
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Dunaief
authors.forename: Judit Z
authors.initials: JZ
authors.lastname: Baffi
authors.forename: Jayakrishna
authors.initials: J
authors.lastname: Ambati
mesh_terms: D020087:Alu Elements / Q000235:genetics*; D000818:Animals; D016923:Cell Death; D002470:Cell Survival; D002478:Cells, Cultured; D053487:DEAD-box RNA Helicases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense; D010641:Phenotype; D012313:RNA / Q000235:genetics* / Q000378:metabolism*; D055213:Retinal Pigment Epithelium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D043244:Ribonuclease III / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D012313:RNA; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases