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B Srinivasan, AM Brun-Zinkernagel, LX Oakford, RJ Collier, MR Al-Ubaidi, PA Barker, RS Roque; Increased Expression and Association of p75NTR and Nrage During Light-Induced Photoreceptor Cell Death . Invest. Ophthalmol. Vis. Sci. 2002;43(13):3726.
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Purpose: The increased levels of the p75 neurotrophin receptor (p75NTR) in animals with retinal degeneration suggest that p75NTR may play a role in photoreceptor cell death. Several p75NTR adaptor proteins, including NRAGE (neurotrophins receptor associated melanoma antigen gene homologue), have been implicated in p75NTR-induced cell death in other systems. In this study, the expression of NRAGE was investigated in in vivo and in vitro systems involving photic injury. Methods: 661w photoreceptor cells were exposed to light (15,000 lux) for 0-5 hrs. and assayed for cell death using neutral red or fluorescent dyes calcein-AM and ethidium homodimer. The expression of NRAGE and p75NTR were determined in 661w cells by immunoblot while levels of p75NTR-bound NRAGE were determined by co-immunoprecipitation. The cellular location of NRAGE protein was determined using immunohistochemistry in rats with photic injury following 6 hrs. of blue-light exposure (220fc). Results: Light exposure of 661w cells at 15,000 lux induced cell death after 3 hrs. of treatment. Increased levels of p75NTR and of two distinct NRAGE bands were observed in immunoblots 1-3 hrs. post-treatment. The association of NRAGE with p75NTR was correspondingly increased in 661w cells exposed to light. Moreover, the intensity of NRAGE immunostaining was increased in photoreceptor outer segments of rats exposed to light for 6 hrs. as compared with control animals. Conclusion: Our study shows that light exposure induces the expression of NRAGE and p75NTR and facilitates their association in cultured photoreceptor cells. In addition, we have shown that photoreceptor cells in the rat retina exhibit increased NRAGE expression in response to photic injury. These studies suggest that the interaction of NRAGE and p75NTR may contribute to photoreceptor cell death in degenerative retinal diseases.
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