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Modeling Neuronal Death and Degeneration in Mouse Primary Cerebellar Granule Neurons
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The roles of Cdk5-mediated subcellular localization of FOXO1 in neuronal death

Jiechao Zhou1, Huifang Li1, Xiaoping Li1

  • 1Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, Medical College, Xiamen University, Xiamen, 361005, Fujian Province, China.

The Journal of Neuroscience : the Official Journal of the Society for Neuroscience
|February 13, 2015
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) deficiency causes neuronal death by allowing the transcription factor FOXO1 into the nucleus, increasing proapoptotic BIM gene expression. Cdk5 normally prevents this by keeping FOXO1 cytoplasmic, thus protecting neurons.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • Cyclin-dependent kinase 5 (Cdk5) is crucial for neuronal development and survival.
  • Cdk5 deficiency is associated with postmitotic cortical neuron death during brain development.

Purpose of the Study:

  • To investigate the role of Cdk5 in regulating the transcription factor FOXO1.
  • To elucidate the mechanism by which Cdk5 influences neuronal survival and death.

Main Methods:

  • In vitro and in vivo phosphorylation assays of FOXO1 by Cdk5.
  • Analysis of FOXO1 localization and transcriptional activity under cellular stress conditions (H2O2, β-amyloid).
  • Assessment of neuronal death and rescue experiments using cytoplasmic FOXO1 variants.

Main Results:

  • Cdk5 phosphorylates FOXO1 at Ser249.
  • Cellular stress leads to Cdk5 hyperactivation, FOXO1 nuclear export, and inhibition of its transcriptional activity.
  • Loss of Cdk5 causes FOXO1 nuclear translocation (independent of S249 phosphorylation), upregulating proapoptotic BIM and leading to neuronal death.
  • Cytoplasmic Cdk5 inhibits FOXO1 activity and BIM expression, preventing neuronal death.

Conclusions:

  • Cdk5 plays a novel role in postmitotic neuron degeneration by controlling FOXO1 cellular localization.
  • Cdk5 deficiency leads to neuronal death via an alternative pathway involving nuclear FOXO1 and BIM upregulation.
  • Modulation of FOXO1 localization by Cdk5 is a key mechanism for neuronal survival.
Keywords:
Cdk5FOXO1neuronal deathphosphorylation

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