Loss of XBP1 Leads to Early-Onset Retinal Neurodegeneration in a Mouse Model of Type I Diabetes

Abstract

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.

Mitochondrial Defects Drive Degenerative Retinal Diseases

“…However, replicating specific aspects of DR pathology is dependent on the model system [See table 1 in 6]. DR pathology mainly includes damage to the microvasculature, but can also effect retinal neurons, as evidenced by changes in the electroretinogram, visual acuity, color sensitivity, and damage to photoreceptors [6,7,8]. Culture models of DR include the use of primary retinal endothelial cells and pericytes, retinal pigment epithelium, Muller cells, or ganglion cells cultured in high glucose.…”

Mastering organismal aging through the endoplasmic reticulum proteostasis network

“…Retinal damage often occurs in diabetic neuropathy, a pathological condition resulting in vision loss in aged adults. Analysis of the progression of retinal degeneration in a mouse model of type I diabetes indicates that the genetic ablation of XBP1 expression in the retina results in an enhanced disruption of photoreceptor function during aging (McLaughlin et al, 2019). However, XBP1 deficiency alone did not provoke spontaneous alterations to retinal function at basal levels.…”

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

“…These are proteins involved in inflammation, oxidative stress, apoptosis, cell survival, endoplasmic reticulum stress response, aging, and other cell processes ( Figure 1 ). These novel biomarkers of DRN include galectin-3 [ 18 , 34 – 36 ] serine racemase (SRR) and its product, D-serine [ 37 – 40 ], REDD1 [ 41 , 42 ], hyperphosphorylated tau [ 43 ], α A-crystallin [ 44 ], SIRT6 [ 45 ], thioredoxin [ 46 , 47 ], CNT [ 48 ], and XBP1 [ 49 ]. They might become promising targets for timely diagnosis and treatment of DRN in the future.…”

“…Another known neuroprotectant, X-box binding protein 1 (XBP1), was recently studied using a conditional retina-specific knockout mouse line. The study demonstrated that depletion of XBP1 in retinal neurons results in early onset retinal function decline, loss of RGCs and photoreceptors, disrupted photoreceptor ribbon synapses, and Müller cell activation after induction of diabetes [ 49 ]. Interestingly, both XBP1 and α A-crystallin are involved in the regulation of the unfolded protein response or endoplasmic reticulum stress response, in which they play key roles to prevent protein aggregation and subsequent cell toxicity and cell death.…”