TY - JOUR
T1 - Cdk5 mediates rotational force-induced brain injury
AU - Umfress, Alan
AU - Chakraborti, Ayanabha
AU - Priya Sudarsana Devi, Suma
AU - Adams, Raegan
AU - Epstein, Daniel
AU - Massicano, Adriana
AU - Sorace, Anna
AU - Singh, Sarbjit
AU - Iqbal Hossian, M.
AU - Andrabi, Shaida A.
AU - Crossman, David K.
AU - Kumar, Nilesh
AU - Shahid Mukhtar, M.
AU - Luo, Huiyang
AU - Simpson, Claire
AU - Abell, Kathryn
AU - Stokes, Matthew
AU - Wiederhold, Thorsten
AU - Rosen, Charles
AU - Lu, Hongbing
AU - Natarajan, Amarnath
AU - Bibb, James A.
N1 - Funding Information:
We thank the UAB Behavioral Assessment Core for assistance, and Carlo Wayan, Curtis Anderson, Jose Becerra, Stacy Donovan, and Athanasios Spiropoulos at UT Dallas Mechanical Engineering Senior Design Program. We thank Divya Shaw and the UT Arlington Mechanical and Aerospace Engineering Dept., and Naveen Varma and the UAB School of Engineering. We thank V. Yang for assistance with data library deposition. We thank the UAB Comprehensive Cancer Center’s Preclinical Imaging Shared Facility (P30CA013148). We thank University of Texas Southwestern Dept of Psychiatry and Carol Tamminga for support of this work. We appreciate the IACUC staffs at UTSW and UAB for help in developing this model.
Funding Information:
This research was facilitated by NINDS T32 Predoctoral Training Fellowship (NS061788) (A.U.). Aspects were supported by pilot funding from the Yale NIDA Neuroproteomics Center (DA018343, A.C.), the DOE (DE-NA 0003962, H.L.) and the University of Texas Louis A. Beachel Jr. endowed Chair (H.L.). This work was also supported by UAB Radiology/CCTS Pilot Research Award. Model development was supported by the Texas Institute for Brain Injury and Repair. Aspects of this work were facilitated by NIH grants NS073855, MH116896, and MH126948 (J.A.B). Aspects of this work were also facilitated by an SDHB Pheo Para Coalition Investigator Award, and an NETRF Accelerator Award.
Funding Information:
We thank the UAB Behavioral Assessment Core for assistance, and Carlo Wayan, Curtis Anderson, Jose Becerra, Stacy Donovan, and Athanasios Spiropoulos at UT Dallas Mechanical Engineering Senior Design Program. We thank Divya Shaw and the UT Arlington Mechanical and Aerospace Engineering Dept., and Naveen Varma and the UAB School of Engineering. We thank V. Yang for assistance with data library deposition. We thank the UAB Comprehensive Cancer Center’s Preclinical Imaging Shared Facility (P30CA013148). We thank University of Texas Southwestern Dept of Psychiatry and Carol Tamminga for support of this work. We appreciate the IACUC staffs at UTSW and UAB for help in developing this model.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.
AB - Millions of traumatic brain injuries (TBIs) occur annually. TBIs commonly result from falls, traffic accidents, and sports-related injuries, all of which involve rotational acceleration/deceleration of the brain. During these injuries, the brain endures a multitude of primary insults including compression of brain tissue, damaged vasculature, and diffuse axonal injury. All of these deleterious effects can contribute to secondary brain ischemia, cellular death, and neuroinflammation that progress for weeks, months, and lifetime after injury. While the linear effects of head trauma have been extensively modeled, less is known about how rotational injuries mediate neuronal damage following injury. Here, we developed a new model of repetitive rotational head trauma in rodents and demonstrated acute and prolonged pathological, behavioral, and electrophysiological effects of rotational TBI (rTBI). We identify aberrant Cyclin-dependent kinase 5 (Cdk5) activity as a principal mediator of rTBI. We utilized Cdk5-enriched phosphoproteomics to uncover potential downstream mediators of rTBI and show pharmacological inhibition of Cdk5 reduces the cognitive and pathological consequences of injury. These studies contribute meaningfully to our understanding of the mechanisms of rTBI and how they may be effectively treated.
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U2 - 10.1038/s41598-023-29322-4
DO - 10.1038/s41598-023-29322-4
M3 - Article
C2 - 36854738
AN - SCOPUS:85149153641
SN - 2045-2322
VL - 13
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 3394
ER -