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Regulation of GSK-3beta by calpain in the 3-nitropropionic acid model

N Crespo-Biel1, A Camins, J Gutiérrez-Cuesta

  • 1Unitat de Farmacologia i Farmacognòsia, Institut de Biomedicina, Facultat de Farmàcia, Universitat de Barcelona, Nucli Universitari de Pedralbes, E-08028 Barcelona, Spain.

Hippocampus
|August 29, 2009
PubMed

Insights

Calpain activation leads to Glycogen synthase kinase-3beta (GSK-3beta) cleavage, a key event in neurodegeneration. Inhibiting calpain protected neurons from 3-nitropropionic acid (3-NP) toxicity, suggesting calpain modulates this process.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Cell Biology

Background:

  • Glycogen synthase kinase-3beta (GSK-3beta) is implicated in neurodegenerative diseases.
  • Calpain-mediated pathways regulate cell death, including that induced by 3-nitropropionic acid (3-NP).
  • GSK-3beta regulation by calpain in the 3-NP model was previously uncharacterized.

Purpose of the Study:

  • To investigate the role of calpain in regulating GSK-3beta during 3-NP-induced neurotoxicity.
  • To examine changes in total GSK-3beta protein levels and phosphorylation at Ser-9.
  • To determine if inhibiting GSK-3beta or cdk5 could prevent 3-NP-induced neuronal loss.

Main Methods:

  • Utilized a 3-nitropropionic acid (3-NP) model of neurodegeneration.
  • Assessed total GSK-3beta protein levels and Ser-9 phosphorylation.
  • Administered calpeptin (calpain inhibitor) and SB-415286 (GSK-3beta inhibitor).
  • Evaluated the impact of cdk5 inhibition on neuronal survival.

Main Results:

  • 3-NP treatment induced GSK-3beta truncation, dependent on calpain activation.
  • Calpeptin prevented GSK-3beta cleavage and 3-NP-induced neuronal loss.
  • Inhibition of GSK-3beta or cdk5 did not rescue neurons from 3-NP toxicity.
  • Findings suggest calpain modulates 3-NP-induced neuronal death.

Conclusions:

  • Calpain activation leads to GSK-3beta cleavage in the 3-NP neurotoxicity model.
  • Calpain, not GSK-3beta inhibition, is protective against 3-NP-induced neuronal loss.
  • Calpain may be a key modulator of 3-NP-induced neurodegeneration, potentially through novel pathways.

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