Department of Optometry and Vision Science, School of Optometry, University of Alabama at Birmingham, Birmingham, AL, USA.
Cell Death Dis. 2018 May 1;9(5):484. doi: 10.1038/s41419-018-0513-1.
An integrated stress response (ISR), identified in several different animal models of inherited retinal degeneration (IRD), is activated following various cellular stresses. The ISR results in the phosphorylation of eIF2α (p-eIF2α) and a consequent halt in protein synthesis. Although generally protective, persistent elevations in p-eIF2α could lead to cell demise. Therefore, we aimed to determine whether ISR activation is associated with diminished translation rates in mice with IRD. Retinal protein extracts from rd16 mice at different time points were analyzed and the retinal levels of protein synthesis were assessed using the SUnSET method. We found that rd16 mice experience persistent ISR activation: p-eIF2α, ATF4, and CHOP were significantly upregulated at P15 and P20. In agreement with ISR activation, we found that rd16 mice experience translational attenuation at P15. Similar to rd16, other IRD models, T17M RHO, and rd10 also demonstrated a decline in protein synthesis, correlating with p-eIF2α elevation. We then assessed the role of PERK and eIF2α in translational attenuation in rd16 using a PERK inhibitor, GSK2606414. We found that while the treatment significantly reduced p-eIF2α, it did not cause a complete recovery in translation. This suggests that eIF2α is not the only or even the primary point of translational control in IRD, and a second node of translational regulation comprising AKT and mTOR should be evaluated. Surprisingly, we found that AKT-mTOR signaling was diminished in rd16 and rd10 retinas, suggesting a potential link between AKT-mTOR and translational inhibition. Therefore, for the first time, this study shows translation attenuation in IRD models, and highlights the potential roles of eIF2α kinases and AKT-mTOR signaling that could grant valuable insight into the potential treatments for IRD.
一个综合应激反应（ISR），在几种不同的遗传性视网膜变性（IRD）动物模型中被识别出来，在各种细胞应激后被激活。ISR 导致 eIF2α 的磷酸化（p-eIF2α），并导致蛋白质合成停止。尽管通常是保护性的，但 p-eIF2α 的持续升高可能导致细胞死亡。因此，我们旨在确定 ISR 激活是否与IRD 小鼠的翻译速率降低有关。在不同时间点从 rd16 小鼠的视网膜蛋白提取物中进行分析，并使用 SUnSET 方法评估视网膜的蛋白质合成水平。我们发现 rd16 小鼠经历持续的 ISR 激活：p-eIF2α、ATF4 和 CHOP 在 P15 和 P20 时显著上调。与 ISR 激活一致，我们发现 rd16 小鼠在 P15 时经历翻译衰减。与 rd16 相似，其他 IRD 模型，T17M RHO 和 rd10 也表现出蛋白质合成的下降，与 p-eIF2α 的升高相关。然后，我们使用 PERK 抑制剂 GSK2606414 评估了 PERK 和 eIF2α 在 rd16 中翻译衰减中的作用。我们发现，虽然治疗显著降低了 p-eIF2α，但它并没有导致翻译的完全恢复。这表明 eIF2α 不是 IRD 中翻译控制的唯一或甚至主要节点，应该评估包括 AKT 和 mTOR 在内的第二个翻译调节节点。令人惊讶的是，我们发现 AKT-mTOR 信号在 rd16 和 rd10 视网膜中减弱，表明 AKT-mTOR 与翻译抑制之间可能存在潜在联系。因此，这项研究首次表明在 IRD 模型中存在翻译衰减，并强调了 eIF2α 激酶和 AKT-mTOR 信号的潜在作用，这可能为 IRD 的潜在治疗方法提供有价值的见解。
