Wang Jing, Saul Alan, Cui Xuezhi, Roon Penny, Smith Sylvia B
Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University, Augusta, Georgia, United States.
The James and Jean Culver Vision Discovery Institute, Augusta University, Augusta, Georgia, United States.
Invest Ophthalmol Vis Sci. 2017 Sep 1;58(11):4545-4558. doi: 10.1167/iovs.17-21947.
Sigma 1 Receptor (Sig1R) is a novel therapeutic target in neurodegenerative diseases, including retinal disease. Sig1R-/- mice have late-onset retinal degeneration with ganglion cell loss that worsens under stress. Whether Sig1R plays a role in maintaining other retinal neurons is unknown, but was investigated here using rd10 mice, a model of severe photoreceptor degeneration.
Wild-type, rd10, and rd10/Sig1R-/- mice were subjected to ERG and spectral-domain optical coherence tomography (SD-OCT) to assess visual function/structure in situ. Retinas imaged microscopically were subjected to morphometric analysis, immunodetection of cones, and analysis of gliosis. Oxidative and endoplasmic reticulum (ER) stress was evaluated at mRNA/protein levels.
Photopic ERG responses were reduced significantly in rd10/Sig1R-/- versus rd10 mice at P28 (31 ± 6 vs. 56 ± 7 μV), indicating accelerated cone loss when Sig1R was absent. At P28, SD-OCT revealed reduced retinal thickness in rd10/Sig1R-/- mice (60% of WT) versus rd10 (80% of WT). Morphometric analysis disclosed profound photoreceptor nuclei loss in rd10/Sig1R-/- versus rd10 mice. rd10/Sig1R-/- mice had 35% and 60% fewer photoreceptors, respectively, at P28 and P35, than rd10. Peanut agglutinin cone labeling decreased significantly; gliosis increased significantly in rd10/Sig1R-/- versus rd10 mice. At P21, NRF2 levels increased in rd10/Sig1R-/- mice versus rd10 and downstream antioxidants increased indicating oxidative stress. At P28, ER stress genes/proteins, especially XBP1, a potent transcriptional activator of the unfolded protein response and CHOP, a proapoptotic transcription factor, increased significantly in rd10/Sig1R-/- mice versus rd10.
Photoreceptor cell degeneration accelerates and cone function diminishes much earlier in rd10/Sig1R-/- than rd10 mice emphasizing the importance of Sig1R as a modulator of retinal cell survival.
西格玛1受体（Sig1R）是神经退行性疾病（包括视网膜疾病）中的一个新型治疗靶点。Sig1R基因敲除小鼠存在迟发性视网膜变性，并伴有神经节细胞丢失，在应激状态下病情会加重。Sig1R是否在维持其他视网膜神经元方面发挥作用尚不清楚，本研究使用严重光感受器变性模型rd10小鼠对此进行了探究。
对野生型、rd10和rd10/Sig1R基因敲除小鼠进行视网膜电图（ERG）和频域光学相干断层扫描（SD-OCT），以原位评估视觉功能/结构。对显微镜下成像的视网膜进行形态计量分析、视锥细胞免疫检测和胶质增生分析。在mRNA/蛋白质水平评估氧化应激和内质网（ER）应激。
在P28时，rd10/Sig1R基因敲除小鼠的明视ERG反应比rd10小鼠显著降低（31±6 vs. 56±7 μV），表明缺乏Sig1R时视锥细胞丢失加速。在P28时，SD-OCT显示rd10/Sig1R基因敲除小鼠的视网膜厚度（为野生型的60%）比rd10小鼠（为野生型的80%）降低。形态计量分析显示，与rd10小鼠相比，rd10/Sig1R基因敲除小鼠的光感受器细胞核大量丢失。在P28和P35时，rd10/Sig1R基因敲除小鼠的光感受器分别比rd10小鼠少35%和60%。花生凝集素视锥细胞标记显著减少；与rd10小鼠相比，rd10/Sig1R基因敲除小鼠的胶质增生显著增加。在P21时，与rd10小鼠相比，rd10/Sig1R基因敲除小鼠的NRF2水平升高，下游抗氧化剂增加，表明存在氧化应激。在P28时，与rd10小鼠相比，rd10/Sig1R基因敲除小鼠中ER应激基因/蛋白质，尤其是未折叠蛋白反应的强效转录激活因子XBP1和促凋亡转录因子CHOP显著增加。
与rd10小鼠相比，rd10/Sig1R基因敲除小鼠的光感受器细胞变性加速，视锥细胞功能更早受损，这强调了Sig1R作为视网膜细胞存活调节剂的重要性。
