Department of Ophthalmology and Visual Sciences, University of Kentucky, Lexington, KY 40506, USA.
Proc Natl Acad Sci U S A. 2012 Aug 21;109(34):13781-6. doi: 10.1073/pnas.1206494109. Epub 2012 Aug 6.
Deficient expression of the RNase III DICER1, which leads to the accumulation of cytotoxic Alu RNA, has been implicated in degeneration of the retinal pigmented epithelium (RPE) in geographic atrophy (GA), a late stage of age-related macular degeneration that causes blindness in millions of people worldwide. Here we show increased extracellular-signal-regulated kinase (ERK) 1/2 phosphorylation in the RPE of human eyes with GA and that RPE degeneration in mouse eyes and in human cell culture induced by DICER1 depletion or Alu RNA exposure is mediated via ERK1/2 signaling. Alu RNA overexpression or DICER1 knockdown increases ERK1/2 phosphorylation in the RPE in mice and in human cell culture. Alu RNA-induced RPE degeneration in mice is rescued by intravitreous administration of PD98059, an inhibitor of the ERK1/2-activating kinase MEK1, but not by inhibitors of other MAP kinases such as p38 or JNK. These findings reveal a previously unrecognized function of ERK1/2 in the pathogenesis of GA and provide a mechanistic basis for evaluation of ERK1/2 inhibition in treatment of this disease.
RNase III DICER1 的表达不足，导致细胞毒性 Alu RNA 的积累，这与年龄相关性黄斑变性（AMD）的晚期地理萎缩（GA）中视网膜色素上皮（RPE）的退化有关，这种疾病导致全世界数百万人失明。在这里，我们发现 GA 患者的 RPE 中细胞外信号调节激酶（ERK）1/2 的磷酸化增加，并且 DICER1 耗竭或 Alu RNA 暴露诱导的小鼠眼睛和人细胞培养中的 RPE 退化是通过 ERK1/2 信号传导介导的。Alu RNA 的过表达或 DICER1 的敲低会增加小鼠和人细胞培养物中 RPE 中的 ERK1/2 磷酸化。通过玻璃体内给予 MEK1 激活激酶 ERK1/2 的抑制剂 PD98059，可挽救 Alu RNA 诱导的小鼠 RPE 退化，但其他 MAP 激酶（如 p38 或 JNK）的抑制剂则无效。这些发现揭示了 ERK1/2 在 GA 发病机制中的先前未被认识的功能，并为评估 ERK1/2 抑制在该疾病治疗中的作用提供了机制基础。
