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Accepted (AM)Open Access (License Unspecified), Open
Journal article
Brain injury-induced proteolysis is reduced in a novel calpastatin overexpressing transgenic mouse
Journal of neurochemistry, v 125(6), pp 909-920
03 Feb 2013
PMID: 23305291
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The calpain family of calcium-dependent proteases has been implicated in a variety of diseases and neurodegenerative pathologies. Prolonged activation of
calpains results in proteolysis of numerous cellular substrates including cytoskeletal components and membrane receptors, contributing to cell demise despite coincident expression of calpastatin, the specific inhibitor of calpains. Pharmacological and gene knockout strategies have targeted calpains to determine their contribution to neurodegenerative pathology; however, limitations associated with treatment paradigms, drug specificity, and genetic disruptions have produced inconsistent results and complicated interpretation. Specific, targeted calpain inhibition achieved by enhancing endogenous calpastatin levels offers unique advantages in studying pathological calpain activation. We have characterized a novel calpastatin overexpressing transgenic
mouse model, demonstrating a substantial increase in calpastatin expression within nervous system and peripheral tissues and associated reduction in protease activity. Experimental activation of calpains via traumatic brain injury resulted in cleavage of α-spectrin, collapsin response mediator protein-2, and voltage-gated sodium channel, critical proteins for the maintenance of neuronal structure and function. Calpastatin overexpression significantly attenuated calpain-mediated proteolysis of these selected substrates acutely following severe controlled cortical impact injury, but with no effect on acute hippocampal neurodegeneration. Augmenting calpastatin levels may be an effective method for calpain inhibition in TBI and neurodegenerative disorders.
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Details
- Title
- Brain injury-induced proteolysis is reduced in a novel calpastatin overexpressing transgenic mouse
- Creators
- Kathleen M. Schoch - University of KentuckyCatherine R. von Reyn - University of PennsylvaniaJifeng Bian - Colorado State UniversityGlenn C. Telling - Colorado State UniversityDavid F. Meaney - University of PennsylvaniaKathryn E. Saatman - University of Kentucky
- Publication Details
- Journal of neurochemistry, v 125(6), pp 909-920
- Publisher
- Wiley
- Number of pages
- 12
- Grant note
- P01 NS056202 || NS / National Institute of Neurological Disorders and Stroke : NINDS P01 NS058484 || NS / National Institute of Neurological Disorders and Stroke : NINDS P30 NS051220 || NS / National Institute of Neurological Disorders and Stroke : NINDS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000320041700011
- Scopus ID
- 2-s2.0-84878757431
- Other Identifier
- 991019176802404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology
- Neurosciences