Zieger Marina, Punzo Claudio
Department of Ophthalmology and Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
Oncotarget. 2016 Mar 1;7(9):9620-33. doi: 10.18632/oncotarget.7330.
Age-related macular degeneration (AMD) is characterized by malfunction and loss of retinal-pigmented epithelium (RPE) cells. Because the RPE transfers nutrients from the choriocapillaris to photoreceptor (PR), PRs are affected as well. Geographic atrophy (GA) is an advanced form of AMD characterized by severe vision impairment due to RPE loss over large areas. Currently there is no treatment to delay the degeneration of nutrient deprived PRs once RPE cells die. Here we show that cell-autonomous activation of the key regulator of cell metabolism, the kinase mammalian target of rapamycin complex 1 (mTORC1), delays PR death in the sodium iodate induced model of RPE atrophy. Consistent with this finding loss of mTORC1 in cones accelerates cone death as cones fail to balance demand with supply. Interestingly, promoting rod survival does not promote cone survival in this model of RPE atrophy as both, rods and cones suffer from a sick and dying RPE. The findings suggest that activation of metabolic genes downstream of mTORC1 can serve as a strategy to prolong PR survival when RPE cells malfunction or die.
年龄相关性黄斑变性（AMD）的特征是视网膜色素上皮（RPE）细胞功能异常和丧失。由于RPE将营养物质从脉络膜毛细血管转运至光感受器（PR），PR也会受到影响。地图样萎缩（GA）是AMD的一种晚期形式，其特征是由于大面积RPE丧失导致严重视力损害。一旦RPE细胞死亡，目前尚无治疗方法可延缓营养缺乏的PR的退化。在此我们表明，细胞代谢关键调节因子——激酶哺乳动物雷帕霉素复合物1靶蛋白（mTORC1）的细胞自主激活，可延缓碘酸钠诱导的RPE萎缩模型中的PR死亡。与这一发现一致，视锥细胞中mTORC1的缺失会加速视锥细胞死亡，因为视锥细胞无法平衡供需。有趣的是，在这个RPE萎缩模型中，促进视杆细胞存活并不能促进视锥细胞存活，因为视杆细胞和视锥细胞都受到病态和濒死RPE的影响。这些发现表明，当RPE细胞功能异常或死亡时，激活mTORC1下游的代谢基因可作为延长PR存活的一种策略。
