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M. Mulhern, K. Ikesugi, R. Yamamoto, J. Usukura, Y. Nishizawa, T. Shinohara; The Unfolded Protein Response (UPR) in RDS Mouse Photoreceptor Degeneration . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1600.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: The role the endoplasmic reticulum (ER) plays in the progression of human diseases has only recently been appreciated. Although a controversy exists as to whether mutant peripherin is expressed or not in the retinal photoreceptor, we hypothesize that a minute level of mutant peripherin is recognized in the ER of the retina degeneration slow (rds/rds–/–) mouse and induces the unfolded protein response (UPR), initiating diverse signaling responses to decrease the accumulated mutant unfolded peripherin. However, if the mutant protein cannot be eliminated, death pathways are activated, resulting in apoptosis. We studied whether the UPR is activated in rds/rds–/– retinal photoreceptors. We also investigated whether the UPR pathway is activated in a retinal 661W cell line after treatment with experimental ER stress inducers. Methods: Retinas from rds/rds–/– mutant mice were prepared and protein blot analysis was conducted with antibodies to various UPR enzymes: GRP78/Bip, ATF4, CHOP, LEDGF, and caspase–12. Murine retinal 661W cells were cultured under three experimental UPR inducers; homocysteine, Ca++ Ionophore (A23187), and tunicamycin and under three environmental–stress conditions; oxidative, heat, and hyperosmotic. Total proteins were extracted from the cells and protein blot analysis was conducted with antibodies to each UPR enzyme. Results: Levels of GRP78/Bip, ATF4 and caspase–12 in retinas from rds/rds–/– mice steadily increased during postnatal days 5, 10, and 15, but not in control C57BL/C mice. Caspase–12 was significantly elevated by day 20 but not in control animals. LEDGF and CHOP were significantly down–regulated during this entire period. Elevated levels of GRP78/Bip and Caspase–12 were found in the retinal 661W cells cultures treated with homocysteine, Ca++ Ionophore, or tunicamycin for 24 hrs. In contrast, retinal 661W cells treated with oxidative–, heat–, and osmotic–stress conditions for 24 hrs did not display elevated levels of GRP78/Bip, CHOP, or caspase–12. Conclusions: Mutant peripherin induces ER stress, which activates the UPR resulting in retinal photoreceptor cell death in rds/rds–/– mice. Activation of the UPR with resulting apoptosis in the retinal 661W cells treated with the experimental ER inducers further confirms this conclusion.
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