Journal article
Neurodegenerative and inflammatory pathway components linked to TNF-α/TNFR1 signaling in the glaucomatous human retina
Investigative ophthalmology & visual science, Vol.52(11), pp.8442-8454
10/31/2011
DOI: 10.1167/iovs.11-8152
PMCID: PMC3208177
PMID: 21917936
Abstract
This study aimed to determine retinal proteomic alterations in human glaucoma, with particular focus on links to TNF-α/TNFR1 signaling. Human retinal protein samples were obtained from 20 donors with (n = 10) or without (n = 10) glaucoma. Alterations in protein expression were individually analyzed by quantitative LC-MS/MS. Quantitative Western blot analysis with cleavage or phosphorylation site-specific antibodies was used for data validation, and cellular localization of selected proteins was determined by immunohistochemical analysis of the retina in an additional group of glaucomatous human donor eyes (n = 38) and nonglaucomatous controls (n = 30). Upregulated retinal proteins in human glaucoma included a number of downstream adaptor/interacting proteins and protein kinases involved in TNF-α/TNFR1 signaling. Bioinformatic analysis of the high-throughput data established extended networks of diverse functional interactions with death-promoting and survival-promoting pathways and mediation of immune response. Upregulated pathways included death receptor-mediated caspase cascade, mitochondrial dysfunction, endoplasmic reticulum stress, calpains leading to apoptotic cell death, NF-κB and JAK/STAT pathways, and inflammasome-assembly mediating inflammation. Interestingly, retinal expression pattern of a regulator molecule, TNFAIP3, exhibited prominent variability between individual samples, and methylation of cytosine nucleotides in the TNFAIP3 promoter was found to be correlated with this variability among glaucomatous donors. Findings of this study reveal a number of proteins upregulated in the glaucomatous human retina that exhibit many links to TNF-α/TNFR1 signaling. By highlighting various signaling molecules and regulators involved in cell death and immune response pathways and by correlating proteomic findings with epigenetic alterations, these findings provide a framework motivating further research.
Details
- Title: Subtitle
- Neurodegenerative and inflammatory pathway components linked to TNF-α/TNFR1 signaling in the glaucomatous human retina
- Creators
- Xiangjun Yang - Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky 40202, USACheng LuoJian CaiDavid W PowellDahai YuMarkus H KuehnGülgün Tezel
- Resource Type
- Journal article
- Publication Details
- Investigative ophthalmology & visual science, Vol.52(11), pp.8442-8454
- DOI
- 10.1167/iovs.11-8152
- PMID
- 21917936
- PMCID
- PMC3208177
- NLM abbreviation
- Invest Ophthalmol Vis Sci
- ISSN
- 0146-0404
- eISSN
- 1552-5783
- Publisher
- United States
- Grant note
- R01 EY019485 / NEI NIH HHS EY019485 / NEI NIH HHS R01 EY013813 / NEI NIH HHS R01 EY017131 / NEI NIH HHS
- Language
- English
- Date published
- 10/31/2011
- Academic Unit
- Ophthalmology and Visual Sciences
- Record Identifier
- 9983980051402771
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