Department of Ophthalmology and Visual Sciences, University of Alberta, 7-45 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada.
Department of Physiology, University of Alberta, 7-45 Medical Sciences Building, Edmonton, AB, T6G 2H7, Canada.
Sci Rep. 2018 Apr 13;8(1):5944. doi: 10.1038/s41598-018-24357-4.
For many neurodegenerative disorders, expression of a pathological protein by one cell type impedes function of other cell types, which in turn contributes to the death of the first cell type. In transgenic mice modelling Stargardt-like (STGD3) maculopathy, human mutant ELOVL4 expression by photoreceptors is associated with defects in the underlying retinal pigment epithelium (RPE). To examine how photoreceptors exert cytotoxic effects on RPE cells, transgenic ELOVL4 (TG1-2 line; TG) and wild-type (WT) littermates were studied one month prior (preclinical stage) to onset of photoreceptor loss (two months). TG photoreceptor outer segments presented to human RPE cells are recognized and internalized into phagosomes, but their digestion is delayed. Live RPE cell imaging pinpoints decreased numbers of acidified phagolysomes. In vivo, master regulator of lysosomal genes, transcription factor EB (TFEB), and key lysosomal enzyme Cathepsin D are both unaffected. Oxidative stress, as ruled out with high-resolution respirometry, does not play a role at such an early stage. Upregulation of CRYBA1/A3 and phagocytic cells (microglia/macrophages) interposed between RPE and photoreceptors support adaptive responses to processing delays. Impaired phagolysosomal maturation is observed in RPE of mice expressing human mutant ELOVL4 in their photoreceptors prior to photoreceptor death and associated vision loss.
对于许多神经退行性疾病，一种细胞类型中病理性蛋白的表达会阻碍其他细胞类型的功能，而这反过来又会导致第一种细胞类型的死亡。在模拟斯塔加德特样（STGD3）黄斑病变的转基因小鼠中，感光细胞中人类突变 ELOVL4 的表达与底层视网膜色素上皮（RPE）的缺陷有关。为了研究感光细胞如何对 RPE 细胞产生细胞毒性作用，研究了转基因 ELOVL4（TG1-2 系；TG）和野生型（WT）同窝仔鼠在感光细胞丢失（两个月）前一个月（临床前阶段）。呈现给人 RPE 细胞的 TG 感光细胞外节被识别并内化到吞噬体中，但它们的消化被延迟。活 RPE 细胞成像确定酸化的吞噬溶酶体数量减少。在体内，溶酶体基因的主要调节因子转录因子 EB（TFEB）和关键溶酶体酶组织蛋白酶 D 均不受影响。高分辨率呼吸测定排除了氧化应激在如此早期阶段不起作用。RPE 中 CRYBA1/A3 和吞噬细胞（小胶质细胞/巨噬细胞）的上调支持对处理延迟的适应性反应。在表达人类突变 ELOVL4 的感光细胞中，在感光细胞死亡和相关视力丧失之前，观察到 RPE 中的吞噬溶酶体成熟受损。
