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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.

SUBMITTER: Kaneko H

PROVIDER: S-EPMC3077055 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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

Kaneko Hiroki H Dridi Sami S Tarallo Valeria V Gelfand Bradley D BD Fowler Benjamin J BJ Cho Won Gil WG Kleinman Mark E ME Ponicsan Steven L SL Hauswirth William W WW Chiodo Vince A VA Karikó Katalin K Yoo Jae Wook JW Lee Dong-ki DK Hadziahmetovic Majda M Song Ying Y Misra Smita S Chaudhuri Gautam G Buaas Frank W FW Braun Robert E RE Hinton David R DR Zhang Qing Q Grossniklaus Hans E HE Provis Jan M JM Madigan Michele C MC Milam Ann H AH Justice Nikki L NL Albuquerque Romulo J C RJ Blandford Alexander D AD Bogdanovich Sasha S Hirano Yoshio Y Witta Jassir J Fuchs Elaine E Littman Dan R DR Ambati Balamurali K BK Rudin Charles M CM Chong Mark M W MM Provost Patrick P Kugel Jennifer F JF Goodrich James A JA Dunaief Joshua L JL Baffi Judit Z JZ Ambati Jayakrishna J

Nature 20110206 7338

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 RN ...[more]

PMID: 21297615

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Project description:Non-exudative age-related macular degeneration, a prevalent cause of blindness, is a progressive and degenerative disease characterized by alterations in Bruch's membrane, retinal pigment epithelium, and photoreceptors exclusively localized in the macula. Although experimental murine models exist, the vast majority take a long time to develop retinal alterations and, in general, these alterations are ubiquitous, with many resulting from non-eye-specific genetic manipulations; additionally, most do not always reproduce the hallmarks of human age-related macular degeneration. Choroid vessels receive sympathetic innervation from the superior cervical ganglion, which, together with the parasympathetic system, regulates blood flow into the choroid. Choroid blood flow changes have been involved in age-related macular degeneration development and progression. At present, no experimental models take this factor into account. The aim of this work was to analyze the effect of superior cervical gangliectomy (also known as ganglionectomy) on the choroid, Bruch's membrane, retinal pigment epithelium and retina. Adult male C57BL/6J mice underwent unilateral superior cervical gangliectomy and a contralateral sham procedure. Although superior cervical gangliectomy induced ubiquitous choroid and choriocapillaris changes, it induced Bruch's membrane thickening, loss of retinal pigment epithelium melanin content and retinoid isomerohydrolase, the appearance of drusen-like deposits, and retinal pigment epithelium and photoreceptor atrophy, exclusively localized in the temporal side. Moreover, superior cervical gangliectomy provoked a localized increase in retinal pigment epithelium and photoreceptor apoptosis, and a decline in photoreceptor electroretinographic function. Therefore, superior cervical gangliectomy recapitulated the main features of human non-exudative age-related macular degeneration, and could become a new experimental model of dry age-related macular degeneration, and a useful platform for developing new therapies.

Dataset Information

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

Publications

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

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