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Oxidative stress triggers neuronal caspase-independent death: endonuclease G involvement in programmed cell

Gavin C Higgins1, Philip M Beart, Phillip Nagley

  • 1Department of Biochemistry and Molecular Biology, Monash University, Building 13D, Clayton Campus, Clayton, VIC 3800, Australia.

Cellular and Molecular Life Sciences : CMLS
|July 8, 2009
PubMed

Insights

Severe oxidative stress triggers a unique form of programmed cell death in neurons, independent of caspases, involving endonuclease G. This finding reveals a novel molecular pathway for neuronal death under oxidative stress.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Neuronal death mechanisms are critical for understanding neurological disorders.
  • Distinguishing between apoptotic and non-apoptotic cell death pathways is essential.
  • Oxidative stress is implicated in various neurodegenerative conditions.

Purpose of the Study:

  • To investigate the mechanisms of neuronal death induced by hydrogen peroxide (H2O2) and staurosporine.
  • To characterize the role of caspases and endonuclease G (Endo G) in these processes.
  • To differentiate between apoptotic and non-apoptotic cell death pathways in primary cortical neurons.

Main Methods:

  • Primary cortical neurons from C57/Black 6 J mice were treated with H2O2 or staurosporine.
  • Cellular changes (shrinkage, nuclear condensation, DNA fragmentation, membrane integrity) were assessed.
  • Caspase activity (caspase-3, caspase-7) was measured.
  • Mitochondrial release of endonuclease G (Endo G) and cytochrome c was analyzed.
  • Endo G expression was suppressed using siRNA to evaluate its role in cell death.

Main Results:

  • Both H2O2 and staurosporine induced classical apoptotic markers like cell shrinkage and DNA fragmentation.
  • Staurosporine activated caspase-3, while H2O2 did not.
  • Both treatments caused the release of Endo G and cytochrome c from mitochondria.
  • siRNA-mediated knockdown of Endo G reduced H2O2-induced nuclear condensation and DNA fragmentation.
  • Endo G suppression protected neurons from H2O2-induced death but only delayed staurosporine-induced death.

Conclusions:

  • Staurosporine induces classical apoptosis in cortical neurons.
  • Severe oxidative stress (H2O2) triggers a caspase-independent, Endo G-dependent form of programmed cell death (programmed cell death-type III) in neurons.
  • Oxidative stress initiates a regulated necrotic pathway in neurons, distinct from apoptosis.

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