Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence.
Photosensitization of A2E triggers telomere dysfunction and accelerates retinal pigment epithelium senescence.
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A2E的光敏作用引发端粒功能障碍并加速视网膜色素上皮衰老
DOI：
10.1038/s41419-017-0200-7
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发表时间：
2018-02-07
影响因子：
9
通讯作者：
Sun X
中科院分区：
文献类型：
--
作者：
Wang J;Feng Y;Han P;Wang F;Luo X;Liang J;Sun X;Ye J;Lu Y;Sun X
视网膜相关性黄斑变性（AMD）是老年人不可逆视力丧失的主要原因。AMD根据临床特征分为早期、中期、晚期非新生血管和晚期新生血管形式。然而，确切的发病机制仍不清楚。视网膜色素上皮（RPE）细胞变性是AMD的标志。随着年龄的增长，脂褐素在RPE细胞中积累。脂褐素的荧光团N-retinylidene-N-retinylethanolamine（A2 E）可能参与RPE细胞的变性。在这项研究中，我们发现A2 E的光敏化增加了DNA损伤，包括端粒脱保护和缺失，并引发细胞衰老。此外，我们发现抗氧化剂N-乙酰半胱氨酸（NAC）部分减轻了这种DNA损伤。端粒酶过表达可挽救A2 E介导的RPE细胞衰老，表明端粒功能障碍在A2 E介导的衰老中起重要作用。我们进一步表明，A2 E光敏诱导的衰老可能通过表达分泌表型（SASP）的几个因子，包括IL 1 B、IL 13 RA 2和CXCR 4，通过NF-κB途径影响视网膜的微环境。我们认为，这些因子的表达创造了一个促炎环境，驱动视网膜变性。此外，我们的研究结果表明，保护端粒是治疗视网膜变性疾病，如AMD的一个有价值的策略。
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in elderly people. AMD is classified as early, intermediate, advanced non-neovascular, and advanced neovascular forms depending on the clinical features. However, the exact pathogenesis remains unclear. Retinal pigment epithelium (RPE) cells degeneration is a hallmark of AMD. With aging, lipofuscin accumulates in RPE cells. N-retinylidene-N-retinylethanolamine (named A2E), a well-known fluorophore of lipofuscin, may contribute to RPE cells degeneration. In this study, we showed that photosensitization of A2E increased DNA damage, including telomere deprotection and deletion, and triggered cellular senescence. In addition, we found that the antioxidant N-acetyl-cysteine (NAC) partially alleviated this DNA damage. Telomerase overexpression rescued A2E-mediated RPE cell senescence, indicating that telomere dysfunction plays an important role in A2E-based senescence. We further showed that the senescence induced by A2E photosensitization may affect the microenvironment of the retina by expressing several factors of the secretory phenotype (SASP) including IL1B, IL13RA2, and CXCR4 through the NF-κB pathway. We propose that expression of these factors create a pro-inflammatory environment that drives retina degeneration. Moreover, our findings suggest that protecting telomeres is a valuable strategy for treating retinal degeneration diseases, such as AMD.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
与年龄相关的黄斑变性中DNA修复蛋白的遗传变异性。
影响因子：
5.6
作者：
Blasiak J;Synowiec E;Salminen A;Kaarniranta K
通讯作者：
Kaarniranta K
影响因子：
64.8
作者：
Baker DJ;Childs BG;Durik M;Wijers ME;Sieben CJ;Zhong J;Saltness RA;Jeganathan KB;Verzosa GC;Pezeshki A;Khazaie K;Miller JD;van Deursen JM
通讯作者：
van Deursen JM
DOI：
10.1136/bjo.2007.123190
发表时间：
2008-04
期刊：
The British journal of ophthalmology
影响因子：
--
作者：
Goverdhan SV;Ennis S;Hannan SR;Madhusudhana KC;Cree AJ;Luff AJ;Lotery AJ
通讯作者：
Lotery AJ
影响因子：
10.5
作者：
Chien, Yuchen;Scuoppo, Claudio;Lowe, Scott W.
通讯作者：
Lowe, Scott W.