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Xiangjun Yang, Cheng Luo, Jian Cai, David W. Powell, Markus H. Kuehn, Gulgun Tezel; A20 Zinc Finger Protein in the Regulation of TNF-α Signaling in Human Glaucoma. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3107.
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Growing evidence supports the involvement of TNF-α signaling in glaucomatous neurodegeneration. Since TNF-α signaling may lead to cell death- or cell survival-promoting diverse bioactivities, ongoing studies using proteomic analysis techniques aim to identify specific target molecules for treatment of glaucoma.
Human retinal protein samples were obtained from age-matched twenty donors with (n:10) or without (n:10) glaucoma and were individually analyzed by quantitative 2D-LC-MS/MS. Western blot analysis was utilized for further validation of the MS/MS data, and the cellular localization of selected proteins was determined by immunohistochemical analysis of an additional group of glaucomatous human donor eyes (n:38) and controls (n:30).
Differentially regulated retinal proteins in human glaucoma included a number of downstream adaptor/interacting proteins and kinases involved in the TNF-α signaling. Bioinformatic analysis of the high-throughput proteomic data established extended functional networks with links to the TNF-α-mediated death- or survival-promoting pathways. An interesting observation was that one of the regulatory molecules, ubiquitin-editing zinc finger protein A20 (also known as Tumor Necrosis Factor Alpha-Induced Protein 3, TNFAIP3), exhibited prominent differences between individual glaucomatous samples. Following set of experiments were focused on this potent inhibitor of NF-ΚB activation and negative regulator of the TNF-α signaling leading to apoptosis, stress response, and inflammation. Quantitative Western blot analysis using a specific antibody validated individual variabilities in A20 expression (over two-fold up-regulation in 4 out of 10 glaucomatous samples versus unchanged or down-regulated expression in rest of the samples). Tissue immunolabeling demonstrated A20 localization in astrocytes and RGCs. Furthermore, the Ingenuity Pathways Analysis pointed out the mechanisms of action that A20 regulates TNF-α-mediated cell death and immunity through diverse interactions with various signaling components (besides NF-ΚB, including those recently associated with glaucomatous neurodegeneration, such as 14-3-3 proteins and toll-like receptors).
These findings highlight many important molecules involved in the TNF-α signaling in human glaucoma. Better understanding of the regulatory pathways of TNF-α signaling, as well as the molecular basis of individual differences, can further benefit the development of new treatment strategies for glaucoma.
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