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M. S. Gorbatyuk, T. Knox, M. M. LaVail, O. Gorbatyuk, S. M. Noorwez, W. W. Hauswirth, J. H. Lin, N. Muzyczka, A. S. Lewin; Activation of the Unfolded Protein Response in a Rat Model of ADRP. Invest. Ophthalmol. Vis. Sci. 2010;51(13):5810.
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Autosomal dominant retinitis pigmentosa (ADRP) is frequently associated with mutation of the gene (Rho) for rod cell opsin. The mechanism of retinal degeneration in P23H rhodopsin photoreceptors is tightly associated with misfolded opsin, which can cause endoplasmic reticulum overload (ER stress), activates the unfolded protein response (UPR) and triggers apoptosis. The goal of this project is to study the ER stress signaling network in transgenic animals to further validate new therapeutic targets for ADRP gene therapy.
We isolated retinas from postnatal day (P) 30 P23H (line 3) Rho transgenic rats and Sprague-Dawley (SD) wild-type rats to study the activation of ER stress signaling by monitoring the peIF2α, sXbp1, CHOP, pATF6, caspase-7 by immunoblots or by RT-PCR.
We found that in P23H Rho rats, photoreceptors levels of cleaved ATF6, pEIF2α, CHOP and caspase-7 were much higher compared to SD rats. For example, in P23H-3 Rhorats, we observed up to a 3-fold increase in the cleaved pATF6 50kD protein, a 51% increase in peIF2α, a 26% increase in the level of CHOP proteinand an almost 4-fold increase in activated caspase-7. At P30 we also observed persistence of the IRE1 pathway in transgenic retinas. The level of spliced Xbp1 mRNA was 4-fold higher in P23HRhoratscompared to wild-type rats.
Our findings indicate that the misfolded opsin activates the UPR signaling in P23H Rho rats and this could be a trigger of apoptosis in ADRP photoreceptors. We also propose that pro-apoptotic CHOP protein and caspase-7 could be potential candidates for the future ADRP gene therapy.
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