Loss of XBP1 Leads to Early-Onset Retinal Neurodegeneration in a Mouse Model of Type I Diabetes
Loss of XBP1 Leads to Early-Onset Retinal Neurodegeneration in a Mouse Model of Type I Diabetes
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DOI：
10.3390/jcm8060906
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发表时间：
2019-06-01
影响因子：
3.9
通讯作者：
Zhang, Sarah X.
中科院分区：
文献类型：
--
作者：
McLaughlin, Todd;Siddiqi, Manhal;Zhang, Sarah X.
视网膜神经元损伤和变性是糖尿病视网膜病变的主要表现之一，是工作年龄成人视力丧失的主要原因。在病理条件下，包括糖尿病和一些生理条件，如衰老，蛋白质稳态可能被破坏，导致内质网（ER）应激。严重或未减轻的ER应激可导致细胞死亡，这在视网膜神经元中导致不可逆的视觉功能丧失。X-box结合蛋白1（X-box binding protein 1，XBP 1）是一种重要的转录因子，在内质网应激时，参与细胞的适应性未折叠蛋白反应（adaptive unfolded protein response，UPR），维持细胞内蛋白质稳态。本研究的目的是确定XBP 1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XBP 1敲除小鼠系，我们证明了视网膜神经元中XBP 1的耗尽导致早期视网膜功能下降，视网膜神经节细胞和光感受器的损失，感光带突触破坏，以及诱导糖尿病后的Muller细胞活化。我们的研究结果表明，在糖尿病视网膜神经元的生存和功能的重要作用，XBP 1介导的适应性UPR。
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 Muller 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.