Ischemic stroke injury is mediated by aberrant Cdk5

Douglas A. Meyer, Melissa I. Torres-Altoro, Zhenjun Tan, Alessandro Tozzi, Massimiliano Di Filippo, Vincent DiNapoli, Florian Plattner, Janice W. Kansy, Stanley A. Benkovic, Jason D. Huber, Diane B. Miller, Paul Greengard, Paolo Calabresi, Charles L. Rosen, James A. Bibb

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

Ischemic stroke is one of the leading causes of morbidity and mortality. Treatment options are limited and only a minority of patients receive acute interventions. Understanding the mechanisms that mediate neuronal injury and death may identify targets for neuroprotective treatments. Here we show that the aberrant activity of the protein kinase Cdk5 is a principal cause of neuronal death in rodents during stroke. Ischemia induced either by embolic middle cerebral artery occlusion (MCAO) in vivo or by oxygen and glucose deprivation in brain slices caused calpain-dependent conversion of the Cdk5-activating cofactor p35 to p25. Inhibition of aberrant Cdk5 during ischemia protected dopamine neurotransmission, maintained field potentials, and blocked excitotoxicity. Furthermore, pharmacological inhibition or conditional knock-out (CKO) of Cdk5 prevented neuronal death in response to ischemia. Moreover, Cdk5 CKO dramatically reduced infarctions following MCAO. Thus, targeting aberrant Cdk5 activity may serve as an effective treatment for stroke.

Original languageEnglish (US)
Pages (from-to)8259-8267
Number of pages9
JournalJournal of Neuroscience
Volume34
Issue number24
DOIs
Publication statusPublished - 2014

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Keywords

  • Biomarker
  • Calpain
  • Cdk5
  • Ischemia
  • Neuroprotection
  • Stroke

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Meyer, D. A., Torres-Altoro, M. I., Tan, Z., Tozzi, A., Filippo, M. D., DiNapoli, V., ... Bibb, J. A. (2014). Ischemic stroke injury is mediated by aberrant Cdk5. Journal of Neuroscience, 34(24), 8259-8267. https://doi.org/10.1523/JNEUROSCI.4368-13.2014