Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 87-99 |
| Number of pages | 13 |
| Journal | Journal of Neurotrauma |
| Volume | 36 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 1 Jan 2019 |
Keywords
- amyotrophic lateral sclerosis
- chronic traumatic encephalopathy
- concussion
- fluid percussion injury
- proteinopathy
Cite this
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Transactive Response DNA-Binding Protein 43 Abnormalities after Traumatic Brain Injury. / Tan, Xin Lin; Sun, Mujun; Brady, Rhys Daniel; Liu, Shijie; Llanos, Roxana M; Cheung, Steve; Wright, David Keith; Casillas-Espinosa, Pablo Miguel; Sashindranath, Maithili; O'Brien, Terence John; McDonald, Stuart J.; Turner, Bradley J; Shultz, Sandy.
In: Journal of Neurotrauma, Vol. 36, No. 1, 01.01.2019, p. 87-99.Research output: Contribution to journal › Article › Research › peer-review
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
VL - 36
SP - 87
EP - 99
JO - Journal of Neurotrauma
JF - Journal of Neurotrauma
SN - 0897-7151
IS - 1
ER -