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Monica K. Ertel, William C. Gordon, Nicolas G. Bazan; Endoplasmic Reticulum (ER) Stress Results In Decreased Levels Of The Peptidyl Prolyl Isomerase Pin1 In P23H Transgenic Rats. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4350.
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The peptidyl prolyl isomerase, Pin1, catalyzes a cis-trans conformational change at phosphorylated Serine-Proline and/or Serine-Threonine bonds, which regulates protein function after phosphorylation. Pin1 has been shown to play a role in neurodegenerative diseases, and Pin1 knockout mice demonstrate a retinal degeneration phenotype. We hypothesized that levels of Pin1 may be decreased in P23H line 3 transgenic rats, and that this plays a role in their retinal degeneration. We also hypothesized that the decreased levels of Pin1 are due to endoplasmic reticulum (ER) stress, which plays a role in the pathogenesis of the retinal degeneration seen in these rats.
To investigate the role of ER stress in decreasing levels of Pin1, we used ARPE-19 cell culture. Cells were treated with 2ug/ml or 5ug/ml tunicamycin for 18 hours to induce ER stress. Following treatment, lysis buffer was added to the plates and the plates were scraped. Western blots were performed using antibodies against p-eIF2α, which is a marker for ER stress. Once ER stress was demonstrated, the membranes were washed and re-stained with antibodies against Pin1. P23H-3 rats were sacrificed at postnatal day 8 (P8), P13, and P15. Control Sprague Dawley rats were sacrificed at P18. Retinas were removed, placed in lysis buffer, and homogenized. Western blots were performed with antibodies targeting Pin1.
We found ARPE-19 cell cultures treated with tunicamycin display increases in p-eIF2α, which confirms that tunicamycin treatment induces ER stress. Tunicamycin treated cells display a concentration dependent decrease in Pin1 levels. Levels of the peptidly propyl isomerase, Pin1, were decreased in P23H rats in comparison to levels in control rats. Pin1 levels varied slightly between the P23H rats depending on age groups; however, all age groups demonstrated a decrease in Pin1 levels in comparison to controls.
Our results suggest that decreased levels of Pin1 play a role in the retinal degeneration seen in the P23H rat model of retinitis pigmentosa as a result of ER stress. Regulation of pathologically induced ER stress may be a potential therapeutic target in retinal degeneration.
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