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Cyclin dependent kinase inhibitors prevent apoptosis of postmitotic mouse motoneurons

A Appert-Collin1, B Hugel, R Levy

  • 1Université Louis Pasteur, Faculté de Pharmacie, UMR7175-LC1, BP 24, F-67401 Illkirch Cedex, France.

Life Sciences
|March 15, 2006
PubMed

Insights

Neuronal death in conditions like ALS may stem from an aborted attempt by post-mitotic neurons to re-enter the cell cycle. Inhibiting cell cycle kinases protected these neurons, supporting this cell cycle re-entry hypothesis.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Apoptosis in post-mitotic neurons is linked to cell cycle re-entry attempts, evidenced by cyclin expression.
  • This cell cycle activation prior to neuronal death is controversial.
  • Neuronal loss in disorders like amyotrophic lateral sclerosis (ALS) may involve inappropriate cell cycle re-entry.

Purpose of the Study:

  • To investigate the role of cell cycle re-entry in neurotrophic factor withdrawal-induced motoneuron apoptosis.
  • To determine if inhibiting cell cycle-dependent kinases (cdks) can prevent motoneuron death.

Main Methods:

  • Purified motoneuron cultures were deprived of neurotrophic factors.
  • Apoptosis was assessed using DAPI staining, apoptotic microparticle release, and caspase activation.
  • The effects of cdk inhibitors (olomoucine, roscovitine, flavopiridol) on motoneuron survival were evaluated.
  • Expression of cyclin D1 and cyclin E was monitored.

Main Results:

  • Neurotrophic factor withdrawal triggered apoptosis, including nuclear condensation, DNA fragmentation, and apoptotic body formation.
  • Apoptotic microparticle release and caspase-3/-9 activation occurred within hours of factor withdrawal.
  • CDK inhibitors significantly suppressed motoneuron death.
  • Early increases in cyclin D1 and cyclin E expression were observed after factor withdrawal.

Conclusions:

  • Motoneuron death induced by trophic factor deprivation involves an inappropriate attempt at cell cycle re-entry.
  • Inhibition of cell cycle-dependent kinases offers a protective strategy against this form of neuronal death.
  • These findings support the hypothesis that aberrant cell cycle re-entry contributes to neuronal loss in neurodegenerative conditions.

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