Dataset Information

Cdk5 mediates rotational force-induced brain injury.

ABSTRACT: 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.

SUBMITTER: Umfress A

PROVIDER: S-EPMC9974974 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Cdk5 mediates rotational force-induced brain injury.

Umfress Alan A Chakraborti Ayanabha A Priya Sudarsana Devi Suma S Adams Raegan R Epstein Daniel D Massicano Adriana A Sorace Anna A Singh Sarbjit S Iqbal Hossian M M Andrabi Shaida A SA Crossman David K DK Kumar Nilesh N Shahid Mukhtar M M Luo Huiyang H Simpson Claire C Abell Kathryn K Stokes Matthew M Wiederhold Thorsten T Rosen Charles C Lu Hongbing H Natarajan Amarnath A Bibb James A JA

Scientific reports 20230228 1

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 ...[more]

PMID: 36854738

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Project description:BackgroundThe integrity of brain function is at stake due to cerebral ischemia-reperfusion injury (CIRI), which encompasses mitochondrial dysfunction, autophagy, and neuroinflammation. The role of E2F1 in mediating these processes in microglia during CIRI remains unclear.MethodsA CIRI mouse model was utilized for single-cell RNA transcriptome sequencing of brain tissues. The research comprised diverse gene expression, gene ontology (GO), and the enrichment of Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Experimental techniques included oxygen-glucose deprivation (OGD/R) cell models, RT-qPCR, Western Blot, ChIP assays, and microglia-neuron co-cultures.ResultsA significant aspect highlighted in the study was the involvement of CDK5 in the induction of mitochondrial abnormalities associated with CIRI. Upregulation of E2F1 and CDK5 in post-CIRI microglia was observed. E2F1 facilitated CDK5 transcription, leading to DRP1 phosphorylation, exacerbating neurotoxic effects. Silencing E2F1 improved neurobehavioral outcomes in CIRI mice.ConclusionsActivation of E2F1-mediated CDK5 drives mitochondrial division while inhibiting mitophagy in microglia, triggering inflammation, neuronal apoptosis, and exacerbating CIRI damage. Targeting this pathway could offer novel therapeutic strategies for mitigating CIRI-induced brain injury.Key pointsIdentification of the E2F1/CDK5/DRP1 Axis in CIRI This study reveals that the E2F1 transcription factor upregulates CDK5 expression, which in turn phosphorylates DRP1, promoting excessive mitochondrial fission and inhibiting mitophagy in microglia. This mechanism plays a critical role in cerebral ischemia-reperfusion injury (CIRI). Mitochondrial Dysfunction and Neuroinflammation The activation of DRP1 leads to mitochondrial fragmentation and excessive ROS accumulation, triggering microglial activation and inflammatory responses, exacerbating neuronal apoptosis and brain injury in CIRI. Therapeutic Potential of E2F1 Silencing Knockdown of E2F1 in microglia effectively reduces mitochondrial damage, restores mitophagy, suppresses inflammation, and improves neurological outcomes in a CIRI mouse model, highlighting a promising therapeutic target for ischemic stroke intervention.

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Cdk5 mediates rotational force-induced brain injury.

Publications

Cdk5 mediates rotational force-induced brain injury.

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