title: Brain injury-induced proteolysis is reduced in a novel calpastatin-overexpressing transgenic mouse.
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 traumatic brain injury and neurodegenerative disorders.
authors.affiliation: Spinal Cord and Brain Injury Research Center and Department of Physiology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0509, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Schoch
authors.forename: Catherine R
authors.initials: CR
authors.lastname: von Reyn
authors.forename: Jifeng
authors.initials: J
authors.lastname: Bian
authors.forename: Glenn C
authors.initials: GC
authors.lastname: Telling
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Saatman
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018703:Founder Effect; D006624:Hippocampus / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D011328:Prions / Q000235:genetics; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D013049:Spectrin / Q000378:metabolism
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D011328:Prions; C095114:collapsin response mediator protein-2; D013049:Spectrin; C033668:calpastatin