Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury

Mohammad A. Yousuf, Chunfeng Tan, Melissa I. Torres-Altoro, Fang Min Lu, Erik Plautz, Shanrong Zhang, Masaya Takahashi, Adan Hernandez, Steven G. Kernie, Florian Plattner, James A. Bibb

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Traumatic brain injury (TBI) is associated with adverse effects on brain functions, including sensation, language, emotions and/or cognition. Therapies for improving outcomes following TBI are limited. A better understanding of the pathophysiological mechanisms of TBI may suggest novel treatment strategies to facilitate recovery and improve treatment outcome. Aberrant activation of cyclin-dependent kinase 5 (Cdk5) has been implicated in neuronal injury and neurodegeneration. Cdk5 is a neuronal protein kinase activated via interaction with its cofactor p35 that regulates numerous neuronal functions, including synaptic remodeling and cognition. However, conversion of p35 to p25 via Ca2+-dependent activation of calpain results in an aberrantly active Cdk5/p25 complex that is associated with neuronal damage and cell death. Here, we show that mice subjected to controlled cortical impact (CCI), a well-established experimental TBI model, exhibit increased p25 levels and consistently elevated Cdk5-dependent phosphorylation of microtubule-associated protein tau and retinoblastoma (Rb) protein in hippocampal lysates. Moreover, CCI-induced neuroinflammation as indicated by increased astrocytic activation and number of reactive microglia. Brain-wide conditional Cdk5 knockout mice (Cdk5 cKO) subjected to CCI exhibited significantly reduced edema, ventricular dilation, and injury area. Finally, neurophysiological recordings revealed that CCI attenuated excitatory post-synaptic potential field responses in the hippocampal CA3-CA1 pathway 24 h after injury. This neurophysiological deficit was attenuated in Cdk5 cKO mice. Thus, TBI induces increased levels of p25 generation and aberrant Cdk5 activity, which contributes to pathophysiological processes underlying TBI progression. Hence, selectively preventing aberrant Cdk5 activity may be an effective acute strategy to improve recovery from TBI. (Figure presented.) Traumatic brain injury (TBI) increases astrogliosis and microglial activation. Moreover, TBI deregulates Ca2+-homeostasis triggering p25 production. The protein kinase Cdk5 is aberrantly activated by p25 leading to phosphorylation of substrates including tau and Rb protein. Loss of Cdk5 attenuates TBI lesion size, indicating that Cdk5 is a critical player in TBI pathogenesis and thus may be a suitable therapeutic target for TBI.

Original languageEnglish (US)
Pages (from-to)317-327
Number of pages11
JournalJournal of Neurochemistry
DOIs
StatePublished - Jul 1 2016

Fingerprint

Cyclin-Dependent Kinase 5
Brain
Chemical activation
tau Proteins
Retinoblastoma Protein
Phosphorylation
Protein Kinases
Cognition
Traumatic Brain Injury
Wounds and Injuries
Brain models
Synaptic Potentials
Calpain
Microtubule-Associated Proteins
Recovery
Microglia
Cell death
Knockout Mice

Keywords

  • cyclin-dependent kinase 5
  • microtubule-associated protein tau
  • neuroinflammation
  • p25
  • retinoblastoma protein
  • traumatic brain injury

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury. / Yousuf, Mohammad A.; Tan, Chunfeng; Torres-Altoro, Melissa I.; Lu, Fang Min; Plautz, Erik; Zhang, Shanrong; Takahashi, Masaya; Hernandez, Adan; Kernie, Steven G.; Plattner, Florian; Bibb, James A.

In: Journal of Neurochemistry, 01.07.2016, p. 317-327.

Research output: Contribution to journalArticle

Yousuf, MA, Tan, C, Torres-Altoro, MI, Lu, FM, Plautz, E, Zhang, S, Takahashi, M, Hernandez, A, Kernie, SG, Plattner, F & Bibb, JA 2016, 'Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury', Journal of Neurochemistry, pp. 317-327. https://doi.org/10.1111/jnc.13620
Yousuf, Mohammad A. ; Tan, Chunfeng ; Torres-Altoro, Melissa I. ; Lu, Fang Min ; Plautz, Erik ; Zhang, Shanrong ; Takahashi, Masaya ; Hernandez, Adan ; Kernie, Steven G. ; Plattner, Florian ; Bibb, James A. / Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury. In: Journal of Neurochemistry. 2016 ; pp. 317-327.
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