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Cdk5 Modulation of mitogen-activated protein kinase signaling regulates neuronal survival

Ya-Li Zheng1, Bing-Sheng Li, Jyotshna Kanungo

  • 1Laboratory of Neurochemistry, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

Molecular Biology of the Cell
|November 17, 2006
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) tightly regulates mitogen-activated protein kinase signaling, crucial for neuronal survival. Dysregulation leads to apoptosis, highlighting Cdk5

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Cyclin-dependent kinase 5 (Cdk5) plays a vital role in neuronal development, migration, and survival.
  • Cdk5 interacts with apoptotic and survival pathways, influencing neuronal cell fate.
  • Previous studies indicated Cdk5-mediated phosphorylation of MEK1 inhibits NGF-induced transient activation in PC12 cells.

Purpose of the Study:

  • To investigate the kinetics of NGF-induced extracellular signal-regulated kinase (Erk)1/2 activation in cortical neurons.
  • To determine the effect of Cdk5 inhibition on Erk1/2 activation and neuronal survival.
  • To elucidate the role of Cdk5 in modulating the mitogen-activated protein kinase pathway for cortical neuron survival.

Main Methods:

  • Studied NGF activation kinetics of Erk1/2 in cortical neurons.
  • Utilized roscovitine, a Cdk5 inhibitor, and PD98095, a MEK1 inhibitor.
  • Employed Cdk5 small interference RNA (siRNA) to knock down Cdk5 activity.
  • Assessed apoptosis and changes in phosphorylated tau and neurofilament localization.

Main Results:

  • NGF induced transient Erk1/2 activation, peaking at 15 min and declining rapidly.
  • Cdk5 inhibition with roscovitine led to sustained Erk1/2 activation for 48 h.
  • Sustained Erk1/2 activation induced apoptosis in cortical neurons.
  • MEK1 inhibition (PD98095) prevented roscovitine-induced apoptosis.
  • Cdk5 knockdown confirmed these findings, correlating apoptosis with altered tau and neurofilament distribution.

Conclusions:

  • Cortical neuron survival depends on Cdk5's precise modulation of the mitogen-activated protein kinase pathway.
  • Aberrant Cdk5 activity disrupts Erk1/2 signaling, promoting apoptosis.
  • Cdk5 acts as a critical regulator, balancing neuronal survival signals.

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