The John A . Moran Eye Center Research and Clinical Abstracts 2010 - 2011
نویسندگان
چکیده
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 a, Subretinal pAlu, but not pNull, induced wild-type mouse RPE degeneration (fundus photographs, top row; ZO-1 stained (red) flat mounts, bottom row). b, Alu RNA induced human RPE cytotoxicity. Values normalized to pNull or vehicle. *P < 0.05 by Student t-test. n = 4–6. c, Subretinal Alu RNA isolated and cloned from human GA RPE induced wild-type mouse RPE degeneration. d, Subretinal injection of this Alu RNA, when cleaved by DICER1, did not induce wild-type mouse RPE degeneration (fundus photographs, top row; flat mounts, bottom row) in contrast to mock-cleaved Alu RNA. Degeneration outlined by blue arrowheads (a, c, d). Scale bars, 20 μm. n = 10–15. R et in al R es ea rc h 3 2 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. Whirlin Replacement Restores the Formation of the USH2 Protein Complex in Whirlin Knockout
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