title: Dual vulnerability of TDP-43 to calpain and caspase-3 proteolysis after neurotoxic conditions and traumatic brain injury.
abstract: Transactivation response DNA-binding protein 43 (TDP-43) proteinopathy has recently been reported in chronic traumatic encephalopathy, a neurodegenerative condition linked to prior history of traumatic brain injury (TBI). While TDP-43 appears to be vulnerable to proteolytic modifications under neurodegenerative conditions, the mechanism underlying the contribution of TDP-43 to the pathogenesis of TBI remains unknown. In this study, we first mapped out the calpain or caspase-3 TDP-43 fragmentation patterns by in vitro protease digestion. Concurrently, in cultured cerebrocortical neurons subjected to cell death challenges, we identified distinct TDP-43 breakdown products (BDPs) of 35, 33, and 12 kDa that were indicative of dual calpain/caspase attack. Cerebrocortical culture incubated with calpain and caspase-fragmented TDP-43 resulted in neuronal injury. Furthermore, increased TDP-43 BDPs as well as redistributed TDP-43 from the nucleus to the cytoplasm were observed in the mouse cortex in two TBI models: controlled cortical impact injury and overpressure blast-wave-induced brain injury. Finally, TDP-43 and its 35 kDa fragment levels were also elevated in the cerebrospinal fluid (CSF) of severe TBI patients. This is the first evidence that TDP-43 might be involved in acute neuroinjury and TBI pathology, and that TDP-43 and its fragments may have biomarker utilities in TBI patients.
authors.affiliation: Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Lin
authors.affiliation: 1] Ben Taub General Hospital, Baylor College of Medicine, Houston, Texas, USA [2] Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Robertson
authors.affiliation: Center for Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
mesh_terms: D000818:Animals; D001930:Brain Injuries / Q000134:cerebrospinal fluid* / Q000473:pathology; D002154:Calpain / Q000134:cerebrospinal fluid*; D053148:Caspase 3 / Q000134:cerebrospinal fluid*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000134:cerebrospinal fluid*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D059748:Proteolysis; D051381:Rats
chemical_list: D002154:Calpain; D053148:Caspase 3; D004268:DNA-Binding Proteins; C578077:Tardbp protein, mouse; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat