title: PrPCexpression and calpain activity independently mediate the effects of closed head injury in mice.
abstract: The normal cellular prion protein (PrPC) is a sialoglycoprotein with a glycophosphatidylinositol anchor and expressed in highest levels within the CNS particularly at neuronal synapses. This membrane-bound protein is involved with many cell functions including cell signaling and neuroprotection. Calpains are calcium-activated cysteine proteases that typically undergo controlled activation. PrPCis a calpain substrate and is neurotoxic if it undergoes aberrant processing with cytosol accumulation. Following traumatic brain injury (TBI), there is an abnormal influx of Ca+2and overactivation of calpains resulting in neuronal dysfunction and cell death. We investigated whether PrPCexpression and calpain activity have an effect on, or are affected by, TBI. PrPCexpression in the hippocampus, cortex and cerebellum of WT and Tga20 (PrPCoverexpression) mice were unchanged after closed head injury (CHI). Further, PrPCin WT and Tga20 mice was resistant to TBI-induced calpain proteolysis. CHI-induced calpain activation resulted in breakdown products (BDPs) of αII-spectrin (SBDPs) and GFAP (GBDP-44K) in all brain regions and mouse lines. CHI caused significant increases in SBDP145, GFAP and GBDP-44K when compared to sham. With few exceptions, the calpain inhibitor, SNJ-1945, reduced SBDP145 and GBDP-44K levels. Behavioral studies suggested that PrPCand calpain independently affect learning and memory. Overall, we conclude that: (i) there is SNJ-1945-sensitive calpain activation in both neuron and glial cells following CHI, (ii) closed head trauma is not affected by, nor does it have an influence on, PrPCexpression, and (iii) PrPCexpression plays a minor role, if any, in CHI-induced calpain activation in vivo.
authors.affiliation: Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box #1213, Brooklyn, NY 11203-2098, USA. Electronic address: Richard.Rubenstein@Downstate.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Rubenstein
authors.affiliation: Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA. Electronic address: Kwang@ufl.edu.
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box #1213, Brooklyn, NY 11203-2098, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Chiu
authors.affiliation: Department of Physiology/Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA.
authors.forename: Natalia
authors.initials: N
authors.lastname: Grinkina
authors.affiliation: Laboratory of Neurodegenerative Diseases and CNS Biomarker Discovery, Departments of Neurology and Physiology/Pharmacology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box #1213, Brooklyn, NY 11203-2098, USA.
authors.forename: Deep R
authors.initials: DR
authors.lastname: Sharma
authors.affiliation: Department of Orthopaedic Surgery and Rehabilitation Medicine, SUNY Downstate Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203-2098, USA.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.affiliation: Program for Neurotrauma, Neuroproteomics and Biomarker Research, Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, FL, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000070642:Brain Injuries, Traumatic / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016489:Head Injuries, Closed / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology
chemical_list: C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; D002219:Carbamates; D004791:Enzyme Inhibitors; D018621:PrPC Proteins; D002154:Calpain
keywords: Calpain; Cellular prion protein; Closed head injury; SNJ-1945; Traumatic brain injury