Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.
Nature. 2011 Mar 17;471(7338):325-30. doi: 10.1038/nature09830. Epub 2011 Feb 6.
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.
地理萎缩（GA）是一种无法治愈的与年龄相关的黄斑变性的晚期形式，是由视网膜色素上皮（RPE）细胞变性引起的。在这里，我们发现 GA 患者的 RPE 中微 RNA（miRNA）加工酶 DICER1 减少，条件性敲除 Dicer1 而不是其他七种 miRNA 加工酶会导致小鼠 RPE 变性。DICER1 的敲低会诱导人 RPE 细胞中 Alu RNA 的积累，并诱导小鼠 RPE 中的 Alu 样 B1 和 B2 RNA。GA 患者的 RPE 中 Alu RNA 增加，这种致病 RNA 会诱导人 RPE 细胞毒性和小鼠 RPE 变性。针对 Alu/B1/B2 RNA 的反义寡核苷酸可以预防 DICER1 耗竭诱导的 RPE 变性，尽管全局 miRNA 下调。DICER1 降解 Alu RNA，而这种消化的 Alu RNA 不能在小鼠中诱导 RPE 变性。这些发现揭示了 DICER1 的 miRNA 非依赖性细胞存活功能，涉及逆转录转座子转录本的降解，表明 Alu RNA 可以直接引起人类疾病，并确定了导致失明的主要原因的新靶点。
