title: Acute and chronically increased immunoreactivity to phosphorylation-independent but not pathological TDP-43 after a single traumatic brain injury in humans.
abstract: The pathologic phosphorylation and sub-cellular translocation of neuronal transactive response-DNA binding protein (TDP-43) was identified as the major disease protein in frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions, now termed FTLD-TDP, and amyotrophic lateral sclerosis (ALS). More recently, TDP-43 proteinopathy has been reported in dementia pugilistica or chronic traumatic encephalopathy caused by repetitive traumatic brain injury (TBI). While a single TBI has been linked to the development of Alzheimer's disease and an increased frequency of neurofibrillary tangles, TDP-43 proteinopathy has not been examined with survival following a single TBI. Using immunohistochemistry specific for both pathological phosphorylated TDP-43 (p-TDP-43) and phosphorylation-independent TDP-43 (pi-TDP-43), we examined acute (n = 23: Survival < 2 weeks) and long-term (n = 39; 1-47 years survival) survivors of a single TBI versus age-matched controls (n = 47). Multiple regions were examined including the hippocampus, medial temporal lobe, cingulate gyrus, superior frontal gyrus and brainstem. No association was found between a history of single TBI and abnormally phosphorylated TDP-43 (p-TDP-43) inclusions. Specifically, just 3 of 62 TBI cases displayed p-TDP-43 pathology versus 2 of 47 control cases. However, while aggregates of p-TDP-43 were not increased acutely or long-term following TBI, immunoreactivity to phosphorylation-independent TDP-43 was commonly increased in the cytoplasm following TBI with both acute and long-term survival. Moreover, while single TBI can induce multiple long-term neurodegenerative changes, the absence of TDP-43 proteinopathy may indicate a fundamental difference in the processes induced following single TBI from those of repetitive TBI.
authors.affiliation: Department of Neurosurgery, Penn Center for Brain Injury and Repair, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Johnson
authors.forename: William
authors.initials: W
authors.lastname: Stewart
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Douglas H
authors.initials: DH
authors.lastname: Smith
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001930:Brain Injuries / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D020208:Brain Injury, Chronic / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D015996:Survival Rate; D057177:TDP-43 Proteinopathies / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins
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