ER Stress in Retinal Degeneration in S334ter Rho Rats

Department of Cell Biology and Anatomy, University of North Texas Health Science Center, North Texas Eye Research Institute, Fort Worth, Texas, United States of America.
PLoS ONE (Impact Factor: 3.53). 03/2012; 7(3):e33266. DOI: 10.1371/journal.pone.0033266
Source: PubMed

ABSTRACT The S334ter rhodopsin (Rho) rat (line 4) bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP). The Unfolded Protein Response (UPR) is implicated in the pathophysiology of several retinal disorders including ADRP in P23H Rho rats. The aim of this study was to examine the onset of UPR gene expression in S334ter Rho retinas to determine if UPR is activated in ADRP animal models and to investigate how the activation of UPR molecules leads to the final demise of S334ter Rho photoreceptors. RT-PCR was performed to evaluate the gene expression profiles for the P10, P12, P15, and P21 stages of the development and progression of ADRP in S334ter Rho photoreceptors. We determined that during the P12-P15 period, ER stress-related genes are strongly upregulated in transgenic retinas, resulting in the activation of the UPR that was confirmed using western blot analysis and RT-PCR. The activation of UPR was associated with the increased expression of JNK, Bik, Bim, Bid, Noxa, and Puma genes and cleavage of caspase-12 that together with activated calpains presumably compromise the integrity of the mitochondrial MPTP, leading to the release of pro-apoptotic AIF1 into the cytosol of S334ter Rho photoreceptor cells. Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells.

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Available from: Marina S Gorbatyuk, Feb 11, 2014
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    • "Hence, ER export has to play a significant role in eye development and vision. However, most studies involving accumulation of rhodopsin in the ER have concentrated on rhodopsin mutations (Kunte et al., 2012; Saliba et al., 2002; Shinde et al., 2012) or on Golgi to plasma membrane transport (Deretic, 2006; Deretic and Wang, 2012). ER-to-Golgi transport has also not been taken into account in models of rhodopsin transport within the inner segment (Karan et al., 2008). "
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