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Many mutations in rhodopsin gene linked to retinitis pigmentosa (RP) cause rhodopsin misfolding. Rod photoreceptor cells expressing misfolded rhodopsin eventually die. Identifying mechanisms to prevent rhodopsin misfolding or to remove irreparably misfolded rhodopsin could provide new therapeutic strategies. IRE1, ATF6, and PERK signaling pathways, collectively called the unfolded protein response (UPR), regulate the functions of endoplasmic reticulum, responsible for accurate folding of membrane proteins such as rhodopsin. We used chemical and genetic approaches to selectively activate IRE1, ATF6, or PERK signaling pathways one at a time and analyzed their effects on mutant rhodopsin linked to RP. We found that both artificial IRE1 and ATF6 signaling promoted the degradation of mutant rhodopsin with lesser effects on wild-type rhodopsin. Furthermore, IRE1 and ATF6 signaling preferentially reduced levels of aggregated rhodopsins. By contrast, PERK signaling reduced levels of wild-type and mutant rhodopsin. These studies indicate that activation of either IRE1, ATF6, or PERK prevents mutant rhodopsin from accumulating in the cells. In addition, activation of IRE1 or ATF6 can selectively remove aggregated or mutant rhodopsin from the cells and may be useful in treating RP associated with rhodopsin protein misfolding. [ABSTRACT FROM AUTHOR]

Rhodopsin mutations cause many types of heritable retinitis pigmentosa (RP). Biochemical and in vitro studies have demonstrated that many RP-linked mutant rhodopsins produce misfolded rhodopsin proteins, which are prone to aggregation and retention within the endoplasmic reticulum, where they cause endoplasmic reticulum stress and activate the Unfolded Protein Response signaling pathways. Many vertebrate models of retinal degeneration have been created through expression of RP-linked rhodopsins in photoreceptors including, but not limited to, VPP/GHL mice, P23HRhodopsin frogs, P23Hrhodopsin rats, S334ter rhodopsin rats, C185R rhodopsin mice, T17M rhodopsin mice, and P23H rhodopsin mice. These models have provided many opportunities to test therapeutic strategies to prevent retinal degeneration and also enabled in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death. Here, we examine and compare the contribution of endoplasmic reticulum stress to retinal degeneration in several vertebrate models of RP generated through expression of mutant rhodopsins. [ABSTRACT FROM AUTHOR]

Oxidative stress or hypoxia is the major disturbance that leads to endoplasmic reticulum (ER) dysfunction. The ER maintains protein homeostasis, including the regulation of the concentration, conformation, folding, and trafficking of client proteins. ER dysfunction by the disturbances such as oxidative stress, referred to as ER stress, induces intracellular stress responses, called the unfolded protein response (UPR). The UPR initially serves as an adaptive response, but also induces apoptosis in cells under severe or prolonged ER stress. The linkage of ER stress with oxidative stress or hypoxia, both of which are pathogenic, indicates the potential pathophysiological significance of ER stress across a wide range of diseases. Accumulating evidence indicates that ER stress contributes to glomerular and tubular damages in patients with acute and chronic kidney diseases. In glomeruli, podocyte or mesangial dysfunction tends to induce the adaptive UPR, which involves ER chaperone expression and the attenuation of protein translation to maintain ER homeostasis and ensure cell survival. In tubules, apoptosis, resulting from epithelial cell damage, is caused by the pro-apoptotic UPR, at least in part. These findings emphasize not only the importance of ER stress as a new progression factor but also the interesting future possibility of renoprotective strategy targeting ER stress. These therapeutic approaches may act by breaking the vicious cycle of oxidative stress, hypoxia, and ER stress. [ABSTRACT FROM AUTHOR]

Endoplasmic Reticulum is a cellular organelle where membrane and extracellular proteins are folded with the help of chaperons. Insulin is one example of such extracellular proteins. Unfolded Protein Response (UPR) is a cell response to an increased level of unfolded proteins in ER. In pancreatic β-cells failure in UPR leads to accumulation of unfolded insulin in Endoplasmic reticulum and eventual cell death. This is thought to be one of the causes of type two diabetes. [ABSTRACT FROM AUTHOR]