Detection of Structural and Metabolic Changes in Traumatically Injured Hippocampus by Quantitative Differential Proteomics
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Traumatic brain injury (TBI) is a complex and common problem resulting in the loss of cognitive function. In order to build a comprehensive knowledge base of the proteins that underlie these cognitive deficits, we employed unbiased quantitative mass spectrometry, proteomics, and bioinformatics to identify and quantify dysregulated proteins in the CA3 subregion of the hippocampus in the fluid percussion model of TBI in rats. Using stable isotope 18O-water differential labeling and multidimensional tandem liquid chromatography (LC)-MS/MS with high stringency statistical analyses and filtering, we identified and quantified 1002 common proteins, with 124 increased and 76 decreased. The ingenuity pathway analysis (IPA) bioinformatics tool identified that TBI had profound effects on downregulating global energy metabolism, including glycolysis, the Krebs cycle, and oxidative phosphorylation, as well as cellular structure and function. Widespread upregulation of actin-related cytoskeletal dynamics was also found. IPA indicated a common integrative signaling node, calcineurin B1 (CANB1, CaNBα, or PPP3R1), which was downregulated by TBI. Western blotting confirmed that the calcineurin regulatory subunit, CANB1, and its catalytic binding partner PP2BA, were decreased without changes in other calcineurin subunits. CANB1 plays a critical role in downregulated networks of calcium signaling and homeostasis through calmodulin and calmodulin-dependent kinase II to highly interconnected structural networks dominated by tubulins. This large-scale knowledge base lays the foundation for the identification of novel therapeutic targets for cognitive rescue in TBI.
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Calcineurin subunit 2 expression decreases following TBI, and its decrease may confer susceptibility to Alzheimer's disease.
“It has been previously reported that calcineurin subunit 2 expression decreases following TBI [165, 166] and its decrease may confer susceptibility to AD [120, 156].”
From Early onset senescence and cognitive impairment in a murine model of repeated mTBI (2021) · cites this paper as [165]
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- Authors
- Wu, P., Zhao, Y., Haidacher, S. J., Wang, E., Parsley, M. O., Gao, J., Sadygov, R. G., Starkey, J. M., Luxon, B. A., Spratt, H., DeWitt, D. S., Prough, D. S., & Denner, L.
- Affiliations
- The University of Texas Medical Branch at Galveston (US)
- Corresponding author
- Denner, Larry
- ORCID
- Venue
- Journal of Neurotrauma
- Publisher
- SAGE Publications
- Published
- 2013-05
- Volume
- 30
- Issue
- 9
- Pages
- 775-788
- ISSN
- 0897-7151 (ISSN-L)
- 1557-9042
- PMC
- PMC3941921
- OpenAlex
- W2058933769
- Cited by
- 36
- References
- 86
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 3 · 2015: 5 · 2014: 4 · 2013: 1
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Journal of Neurotrauma (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Moody Foundation
- National Institutes of Health (UL1TR000071)
- National Center for Advancing Translational Sciences
- U.S. Army Medical Research Acquisition Activity
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- traumatic brain injury, hippocampus, fluid percussion injury, differential proteomics, energy metabolism, glycolysis, TCA cycle, oxidative phosphorylation, cytoskeletal dynamics, actin, PPP3R1, calcium signaling, calmodulin, calmodulin-dependent kinase II, tubulin, cognitive impairment, therapeutic target
- MeSH terms
- Animals, Brain Injuries, Chromatography, Liquid, Disease Models, Animal, Hippocampus, Male, Blotting, Western, Rats, Sprague-Dawley, Calcineurin, Proteomics, Rats, Tandem Mass Spectrometry
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