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- Title
Involvement of aberrant cyclin-dependent kinase 5/p25 activity in experimental traumatic brain injury.
- Authors
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.
- 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.
- Subjects
CYCLINS; GROWTH factors; CYCLIN-dependent kinases; KINASES; PHOSPHOTRANSFERASES
- Publication
Journal of Neurochemistry, 2016, Vol 138, Issue 2, p317
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.13620