McLaughlin Todd, Siddiqi Manhal, Wang Joshua J, Zhang Sarah X
Departments of Ophthalmology and Ross Eye Institute, University at Buffalo, Buffalo, NY 14203, USA.
SUNY Eye Institute, State University of New York, Buffalo, NY 14203, USA.
J Clin Med. 2019 Jun 25;8(6):906. doi: 10.3390/jcm8060906.
Retinal neuronal injury and degeneration is one of the primary manifestations of diabetic retinopathy, a leading cause of vision loss in working age adults. In pathological conditions, including diabetes and some physiological conditions such as aging, protein homeostasis can become disrupted, leading to endoplasmic reticulum (ER) stress. Severe or unmitigated ER stress can lead to cell death, which in retinal neurons results in irreversible loss of visual function. X-box binding protein 1 (XBP1) is a major transcription factor responsible for the adaptive unfolded protein response (UPR) to maintain protein homeostasis in cells undergoing ER stress. The purpose of this study is to determine the role of XBP1-mediated UPR in retinal neuronal survival and function in a mouse model of type 1 diabetes. Using a conditional retina-specific XBP1 knockout mouse line, we demonstrate that depletion of XBP1 in retinal neurons results in early onset retinal function decline, loss of retinal ganglion cells and photoreceptors, disrupted photoreceptor ribbon synapses, and Müller cell activation after induction of diabetes. Our findings suggest an important role of XBP1-mediated adaptive UPR in retinal neuronal survival and function in diabetes.
视网膜神经元损伤和变性是糖尿病性视网膜病变的主要表现之一，糖尿病性视网膜病变是工作年龄成年人视力丧失的主要原因。在包括糖尿病在内的病理状况以及一些生理状况（如衰老）下，蛋白质稳态可能会被破坏，从而导致内质网（ER）应激。严重或未缓解的ER应激可导致细胞死亡，这在视网膜神经元中会导致视觉功能的不可逆丧失。X盒结合蛋白1（XBP1）是一种主要的转录因子，负责适应性未折叠蛋白反应（UPR），以在经历ER应激的细胞中维持蛋白质稳态。本研究的目的是确定XBP1介导的UPR在1型糖尿病小鼠模型中视网膜神经元存活和功能中的作用。使用条件性视网膜特异性XBP1基因敲除小鼠品系，我们证明在糖尿病诱导后，视网膜神经元中XBP1的缺失会导致视网膜功能早期下降、视网膜神经节细胞和光感受器丧失、光感受器带状突触破坏以及Müller细胞激活。我们的研究结果表明XBP1介导的适应性UPR在糖尿病中视网膜神经元存活和功能中起重要作用。
