The retina, as part of the central nervous system (CNS) with limited capacity for self-reparation and regeneration in mammals, is under cumulative environmental stress due to high-energy demands and rapid protein turnover. These stressors disrupt the cellular protein and metabolic homeostasis, which, if not alleviated, can lead to dysfunction and cell death of retinal neurons. One primary cellular stress response is the highly conserved unfolded protein response (UPR). The UPR acts through three main signaling pathways in an attempt to restore the protein homeostasis in the endoplasmic reticulum (ER) by various means, including but not limited to, reducing protein translation, increasing protein-folding capacity, and promoting misfolded protein degradation. Moreover, recent work has identified a novel function of the UPR in regulation of cellular metabolism and mitochondrial function, disturbance of which contributes to neuronal degeneration and dysfunction. The role of the UPR in retinal neurons during aging and under disease conditions in age-related macular degeneration (AMD), retinitis pigmentosa (RP), glaucoma, and diabetic retinopathy (DR) has been explored over the past two decades. Each of the disease conditions and their corresponding animal models provide distinct challenges and unique opportunities to gain a better understanding of the role of the UPR in the maintenance of retinal health and function. We performed an extensive literature search on PubMed and Google Scholar using the following keywords: unfolded protein response, metabolism, ER stress, retinal degeneration, aging, age-related macular degeneration, retinitis pigmentosa, glaucoma, diabetic retinopathy. We summarize recent advances in understanding cellular stress response, in particular the UPR, in retinal diseases, highlighting the potential roles of UPR pathways in regulation of cellular metabolism and mitochondrial function in retinal neurons. Further, we provide perspective on the promise and challenges for targeting the UPR pathways as a new therapeutic approach in age- and disease-related retinal degeneration.

中文翻译：

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视网膜变性中的细胞应激信号和未折叠蛋白反应：机制和治疗意义

视网膜作为中枢神经系统 (CNS) 的一部分，哺乳动物的自我修复和再生能力有限，由于高能量需求和快速蛋白质周转，视网膜处于累积的环境压力之下。这些压力源会破坏细胞蛋白质和代谢稳态，如果不加以缓解，可能会导致视网膜神经元功能障碍和细胞死亡。一种主要的细胞应激反应是高度保守的未折叠蛋白反应 (UPR)。UPR 通过三个主要信号通路发挥作用，试图通过各种方式恢复内质网 (ER) 中的蛋白质稳态，包括但不限于减少蛋白质翻译、增加蛋白质折叠能力和促进错误折叠的蛋白质降解。而且，最近的工作确定了 UPR 在调节细胞代谢和线粒体功能方面的新功能，其干扰会导致神经元退化和功能障碍。在过去的二十年中，已经探索了 UPR 在衰老过程中以及在年龄相关性黄斑变性 (AMD)、视网膜色素变性 (RP)、青光眼和糖尿病性视网膜病变 (DR) 疾病条件下视网膜神经元中的作用。每种疾病状况及其相应的动物模型都提供了独特的挑战和独特的机会，以更好地了解 UPR 在维持视网膜健康和功能中的作用。我们使用以下关键词对 PubMed 和 Google Scholar 进行了广泛的文献搜索：未折叠蛋白反应、新陈代谢、内质网应激、视网膜变性、衰老、年龄相关性黄斑变性、色素性视网膜炎、青光眼、糖尿病性视网膜病变。我们总结了理解视网膜疾病中细胞应激反应，特别是 UPR 的最新进展，强调了 UPR 通路在调节视网膜神经元细胞代谢和线粒体功能中的潜在作用。此外，我们提供了关于将 UPR 通路作为一种新的治疗与年龄和疾病相关的视网膜变性的方法的前景和挑战的观点。