Department of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK.
MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
Cells. 2021 Nov 7;10(11):3066. doi: 10.3390/cells10113066.
Cholesterol dysregulation has been implicated in age-related macular degeneration (AMD), the most common cause of visual impairment in the elderly. The 18 KDa translocator protein (TSPO) is a mitochondrial outer membrane protein responsible for transporting cholesterol from the mitochondrial outer membrane to the inner membrane. TSPO is highly expressed in retinal pigment epithelial (RPE) cells, and TSPO ligands have shown therapeutic potential for the treatment of AMD. Here, we characterized retinal pathology of knockout (KO) mice using histological, immunohistochemical, biochemical and molecular biological approaches. We found that KO mice had normal retinal morphology (by light microscopy) but showed elevated levels of cholesterol, triglycerides and phospholipids with perturbed cholesterol efflux in the RPE cells of KO mice. Expression of cholesterol-associated genes (, , , and ) was significantly downregulated, and production of pro-inflammatory cytokines was markedly increased in KO retinas. Furthermore, microglial activation was also observed in KO mouse retinas. These findings provide new insights into the function of TSPO in the retina and may aid in the design of new therapeutic strategies for the treatment of AMD.
胆固醇失调与年龄相关性黄斑变性（AMD）有关，AMD 是老年人视力损害的最常见原因。18 kDa 转位蛋白（TSPO）是一种位于线粒体外膜的蛋白，负责将胆固醇从线粒体外膜转运到内膜。TSPO 在视网膜色素上皮（RPE）细胞中高度表达，TSPO 配体在治疗 AMD 方面显示出治疗潜力。在这里，我们使用组织学、免疫组织化学、生化和分子生物学方法来描述 敲除（KO）小鼠的视网膜病理学。我们发现 KO 小鼠的视网膜形态正常（通过光镜检查），但 RPE 细胞中的胆固醇、甘油三酯和磷脂水平升高，胆固醇外排受到干扰。胆固醇相关基因（、、、和）的表达显著下调，KO 视网膜中促炎细胞因子的产生明显增加。此外，还观察到 KO 小鼠视网膜中的小胶质细胞激活。这些发现为 TSPO 在视网膜中的功能提供了新的见解，并可能有助于设计治疗 AMD 的新治疗策略。
