TY - JOUR
T1 - Transactive Response DNA-Binding Protein 43 Abnormalities after Traumatic Brain Injury
AU - Tan, Xin Lin
AU - Sun, Mujun
AU - Brady, Rhys Daniel
AU - Liu, Shijie
AU - Llanos, Roxana M
AU - Cheung, Steve
AU - Wright, David Keith
AU - Casillas-Espinosa, Pablo Miguel
AU - Sashindranath, Maithili
AU - O'Brien, Terence John
AU - McDonald, Stuart J.
AU - Turner, Bradley J
AU - Shultz, Sandy
PY - 2019/1/1
Y1 - 2019/1/1
N2 - Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis (ALS), a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes. Further, how TBI affects an individual with a known predisposition to TDP-43 pathology is unknown. Therefore, this study examined the effects of TBI on TDP-43 post-translational processing, localization, and behavioral outcomes in wild-type (WT) mice and mutant TDP-43A315T mice (i.e., mice predisposed to TDP-43 pathology) at 24 h and 1 week after TBI. Post-mortem brain tissue from human patients with acute TBI was also examined. Western blots found that WT mice given TBI had increased TDP-43 phosphorylation, mislocalization, and fragmentation compared with sham-injured WT mice. The TDP-43A315T mice given a TBI had exacerbated TDP-43 abnormalities, worse cell death, and cognitive deficits compared with all other groups. In the human TBI patients, the only significant finding was increased nuclear accumulation of phosphorylated TDP-43 fragments. The discrepancy between the robust mouse findings and the largely non-significant human findings may be due to factors including heterogeneity in clinical TBI, the small group sizes, and temporal complexities with TDP-43 abnormalities. These findings indicate that TBI can induce a number of TDP-43 abnormalities that may contribute to the neurological consequences of TBI, though further research is still needed.
AB - Initial studies have found some evidence for transactive response DNA-binding protein 43 (TDP-43) abnormalities after traumatic brain injury (TBI), and the presence of protein inclusions consisting of TDP-43 are a pathological hallmark of amyotrophic lateral sclerosis (ALS), a condition associated with TBI. However, no study has characterized changes in TDP-43 phosphorylation, mislocalization, and fragmentation (i.e., abnormalities linked to hallmark TDP-43 pathology) after TBI, and how these relate to functional outcomes. Further, how TBI affects an individual with a known predisposition to TDP-43 pathology is unknown. Therefore, this study examined the effects of TBI on TDP-43 post-translational processing, localization, and behavioral outcomes in wild-type (WT) mice and mutant TDP-43A315T mice (i.e., mice predisposed to TDP-43 pathology) at 24 h and 1 week after TBI. Post-mortem brain tissue from human patients with acute TBI was also examined. Western blots found that WT mice given TBI had increased TDP-43 phosphorylation, mislocalization, and fragmentation compared with sham-injured WT mice. The TDP-43A315T mice given a TBI had exacerbated TDP-43 abnormalities, worse cell death, and cognitive deficits compared with all other groups. In the human TBI patients, the only significant finding was increased nuclear accumulation of phosphorylated TDP-43 fragments. The discrepancy between the robust mouse findings and the largely non-significant human findings may be due to factors including heterogeneity in clinical TBI, the small group sizes, and temporal complexities with TDP-43 abnormalities. These findings indicate that TBI can induce a number of TDP-43 abnormalities that may contribute to the neurological consequences of TBI, though further research is still needed.
KW - amyotrophic lateral sclerosis
KW - chronic traumatic encephalopathy
KW - concussion
KW - fluid percussion injury
KW - proteinopathy
UR - http://www.scopus.com/inward/record.url?scp=85059066072&partnerID=8YFLogxK
U2 - 10.1089/neu.2017.5491
DO - 10.1089/neu.2017.5491
M3 - Article
AN - SCOPUS:85059066072
VL - 36
SP - 87
EP - 99
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
SN - 0897-7151
IS - 1
ER -