<i>TNFRSF10A</i> downregulation induces retinal pigment epithelium degeneration during the pathogenesis of age-related macular degeneration and central serous chorioretinopathy
<i>TNFRSF10A</i> downregulation induces retinal pigment epithelium degeneration during the pathogenesis of age-related macular degeneration and central serous chorioretinopathy
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在年龄相关性黄斑变性和中心性浆液性脉络膜视网膜病变的发病机制中，<i>TNFRSF10A</i>下调诱导视网膜色素上皮变性
DOI：
10.1093/hmg/ddac020
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发表时间：
2022
影响因子：
3.5
通讯作者：
Sonoda Koh-Hei
中科院分区：
文献类型：
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作者：
Mori Kenichiro;Ishikawa Keijiro;Fukuda Yosuke;Ji Rui;Wada Iori;Kubo Yuki;Akiyama Masato;Notomi Shoji;Murakami Yusuke;Nakao Shintaro;Arakawa Satoshi;Shiose Satomi;Hisatomi Toshio;Yoshida Shigeo;Kannan Ram;Sonoda Koh-Hei
年龄相关性黄斑变性 (AMD) 和中心性浆液性脉络膜视网膜病变 (CSC) 是可导致老年人和年轻人视力丧失的常见疾病。这些疾病都有源自视网膜色素上皮 (RPE) 功能障碍的病理生理学状况。具有相同先导单核苷酸多态性 (SNP) (rs13278062) 的肿瘤坏死因子受体超家族 10A (TNFRSF10A)-LOC389641 是通过全基因组关联研究在 AMD 和 CSC 中发现的唯一重叠易感性位点。据报道，该先导 SNP 可改变 TNFRSF10A 的转录活性。本研究旨在利用人原代 RPE 细胞和 Tnfrsf10 敲除 (Tnfrsf10−/−) 小鼠阐明 TNFRSF10A 在 RPE 变性中的功能。 TNFRSF10A 被发现位于人类 RPE 中。体外分析显示，AMD 和 CSC 的风险等位基因 rs13278062 的 T 等位基因下调 RPE 中的 TNFRSF10A 转录，通过蛋白激酶 C-α (PKCA) 下调导致细胞活力下降和细胞凋亡增加。用佛波醇 12-肉豆蔻酸酯 13-乙酸酯（一种 PKC 激活剂）治疗可恢复细胞活力。在Tnfrsf10−/−小鼠的视网膜中发现形态RPE异常。我们的数据表明，TNFRSF10A 表达下调会使 PKCA 信号失活并导致 RPE 的细胞脆弱性，这可能有助于 AMD 和 CSC 的发病机制。
Age-related macular degeneration (AMD) and central serous chorioretinopathy (CSC) are common diseases that can cause vision loss in older and younger populations. These diseases share pathophysiological conditions derived from retinal pigment epithelium (RPE) dysfunction. Tumor necrosis factor receptor superfamily 10A (TNFRSF10A)-LOC389641 with the same lead single-nucleotide polymorphism (SNP) (rs13278062) is the only overlapped susceptibility locus found in both AMD and CSC through genome-wide association studies. This lead SNP has been reported to alter the transcriptional activity ofTNFRSF10A. This study aimed to elucidate the function of TNFRSF10A in RPE degeneration using human primary RPE cells and Tnfrsf10 knockout (Tnfrsf10−/−) mice. TNFRSF10A was found to be localized in human RPE.In vitroassays revealed that a T allele of rs13278062, the risk allele for AMD and CSC, downregulatedTNFRSF10Atranscription in RPE, leading to decreased cell viability and increased apoptosis through protein kinase C-α (PKCA) downregulation. Treatment with phorbol 12-myristate 13-acetate, a PKC activator, rescued the cell viability. Morphological RPE abnormality was found in the retina ofTnfrsf10−/−mice. Our data suggest that downregulation ofTNFRSF10Aexpression inactivates PKCA signaling and causes cellular vulnerability of the RPE, which may contribute to the pathogenesis of AMD and CSC.