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Xiangjun Yang, Jian Cai, David Powell, Markus Kuehn, Gulgun Tezel; Up-regulation of autophagy in the glaucomatous human retina. Invest. Ophthalmol. Vis. Sci. 2013;54(15):409.
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Recent studies of experimental rat glaucoma have indicated autophagy activation during glaucomatous neurodegeneration. To determine whether autophagy is activated in the glaucomatous human retina, we analyzed the high-throughput proteomics data from human donor eyes in correlation to retinal immunolabeling patterns of selected autophagy-linked proteins.
Retinal protein samples obtained from human donors with (n:10) or without (n:10) glaucoma were quantitatively analyzed by label-free 2D-LC-MS/MS. To validate proteomics findings, Western blot analysis determined the expression level of two autophagy-enabling proteins, microtubule-associated protein 1A/1B-light chain 3 (LC3) and beclin. In addition, the extent and cellular localization of these proteins were determined by immunohistochemical analysis of retina sections obtained from an additional group of human donor eyes with glaucoma (n:34) and non-glaucomatous controls (n:20).
Quantitative proteomics analysis indicated the up-regulated profile of a number of proteins linked to autophagy in the glaucomatous human retina. These proteins included autophagy proteins required for autophagosome formation, including ATG4, ATG5, ATG7, and LC3-I (ATG8), and negative regulatory proteins, including mammalian target of rapamycin (mTOR) and regulatory-associated protein of mTOR (raptor). Western blot analysis and immunohistochemical analysis validated the proteomics data and indicated an over two-fold up-regulation of the membrane-bound processed form of LC3 (LC3-II) and beclin (ATG6) in the glaucomatous retinas relative to non-glaucomatous controls.
Up-regulation of LC3-II and beclin, established as autophagy-enabling events, supports autophagic activation in the glaucomatous human retina. Although up-regulation of autophagy is a cell-protection mechanism, under specific conditions, it may become an alternative cell-death mechanism or induce autoimmunity. It remains unclear whether autophagic activity reflects a sufficient intrinsic response to meet the increasing demand to maintain cellular homeostasis during glaucomatous stress/injury, or it is inefficient as a native defense mechanism, or its potential dysregulation compromises the cell survival and/or immune homeostasis. Findings of this study motivate further research to explore the cell-specific regulation of autophagy and implications in neurodegenerative and neuroinflammatory processes of glaucoma.
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