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B. Rohrer, K. Hulse, A.K. Sharma, Y. Guo, H.R. Lohr; Common Pathways in Photoreceptor Cell Death in Mouse Models of Retinitis Pigmentosa . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1665.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Human photoreceptor dystrophies have been associated with mutations in 156 different genes (RetNet at http://www.retnet.org) and with multiple environmental factors. This diversity has hampered the development of treatment strategies as investigators have worked to identify potential rescue factors for individual target genes in the retina. Here we address the question whether there exist common clusters of genes that influence the degenerative response in diverse rod dystrophies. Methods: Three models of photoreceptor degeneration were chosen: the rd mouse (Farber, 1995) in which rods are presumed to die due to calcium toxicity (Fox et al., 1999); the rds mouse (Travis et al., 1989), which fail to develop outer segments; and light–damage (LD; reviewed in Penn and Anderson, 1991), which causes oxidative stress. To identify pathways involved in cell death, we evaluated gene expression in the rd, rds and LD and their respective wild type mouse retinas using U74A oligonucleatide arrays (Affymetrix) at two time points (early and late) during the known time course of photoreceptor degeneration. Selected genes were verified at the mRNA level using the QuantiTect Syber Green PCR Kit, and at the protein level using enzymatic assays. Results: (A) Venn analysis revealed that early in the degenerative process, very few common genes were identified, suggesting that degeneration is triggered by private pathways. (B) During the execution phase of cell death a total of 112 co–regulated genes could be identified. Average linkage analysis based on expression data, identified 6 distinct gene clusters. Clusters 4 and 5 contain the genes that appear to define the genes that make up the common degenerative pathways. All three insults lead to the upregulation of genes involved in neuroinflammation (e.g. complement system; TNFα signaling, GFAP), oxidative stress (e.g. metallothionein, ceruloplasmin), and apoptosis/autophagy (e.g. proteosome, lysozyme, cathepsin S). Based on the known actions of these gene’s products, it is reasonable to hypothesize that the common secondary degenerative events include oxidative stress, neuroinflammation, autophagy and apoptosis. (C) The involvement of autophagy and apoptosis as mechanisms of cell death was verified by enzymatic assays. Conclusions: Our results suggest that rod cell death is triggered by individual primary insults, but involves common secondary events. Common pathways in neurodegeneration have important implications for therapeutic strategies.
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