Endoplasmic reticulum stress and the unfolded protein responses in retinal degeneration

Abstract

The endoplasmic reticulum (ER) is the primary intracellular organelle responsible for protein and lipid biosynthesis, protein folding and trafficking, calcium homeostasis, and several other vital processes in cell physiology. Disturbance in ER function results in ER stress and subsequent activation of the unfolded protein response (UPR). The UPR up-regulates ER chaperones, reduces protein translation, and promotes clearance of cytotoxic misfolded proteins to restore ER homeostasis. If this vital process fails, the cell will be signaled to enter apoptosis, resulting in cell death. Sustained ER stress also can trigger an inflammatory response and exacerbate oxidative stress, both of which contribute synergistically to tissue damage. Studies performed over the past decade have implicated ER stress in a broad range of human diseases, including neurodegenerative diseases, cancer, diabetes, and vascular disorders. Several of these diseases also entail retinal dysfunction and degeneration caused by injury to retinal neurons and/or to the blood vessels that supply retinal cells with nutrients, trophic and homeostatic factors, oxygen, and other essential molecules, as well as serving as a conduit for removal of waste products and potentially toxic substances from the retina. Collectively, such injuries represent the leading cause of blindness world-wide in all age groups. Herein, we summarize recent progress on the study of ER stress and UPR signaling in retinal biology and discuss the molecular mechanisms and the potential clinical applications of targeting ER stress as a new therapeutic approach to prevent and treat neuronal degeneration in the retina.

Supplementation of procyanidins B2 attenuates photooxidation-induced apoptosis in ARPE-19 cells

“…GRP78 may interact with apoptosis pathway by blocking caspase activation and reducing CHOP expression (Gorbatyuk et al 2010). A role for the UPR in oxidative stress control and cell survival has been demonstrated in RPE Zhang et al 2014). PB2 inhibited apoptosis in a GRP78-dependent manner, suggesting UPR response is required.…”

The Mitochondrial Complex I Inhibitor Rotenone Induces Endoplasmic Reticulum Stress and Activation of GSK-3β in Cultured Rat Retinal Cells

“…27 In a rat model of chronic glaucoma, both phospho-PERK and CHOP were detected in ganglion cells, accompanied by TUNEL-positive cells and decreased number of ganglion cells. 28 Similar results could also be found in a rat retinal ischemia-reperfusion downregulation of inactive p-GSK-3b (Ser 9 ) following treatment with rotenone (1 lM) for 0, 1, 2, 3, 6, and 24 hours as determined by Western blotting.…”

“…model 29 and an excitotocity paradigm of ganglion cell death. 27 All these animal models have a relatively chronic or moderate ATP loss. However, in our acute mitochondrial injury model, it is interesting to note that even though mixed retinal cell cultures containing both glia and neurons 30 were severely depleted of their ATP levels by rotenone, the vimentin-rich retinal glial cell cultures (28 days in vitro) were relatively unaffected.…”

Achromatopsia mutations target sequential steps of ATF6 activation

“…Patient fibroblasts with several of these mutations showed increased sensitivity to ER stressinduced cell death and damage. Diverse environmental insults have been found to trigger ER stress, including hypoxia, infection, inflammation, protein misfolding, and light damage (27)(28)(29)(30)(31)(32)(33). Exposure to these insults during retinal development may contribute to the cone dysfunction and vision loss that arises in children with mutations that compromise ATF6 function.…”