p38MAPK/p53 signalling axis mediates neuronal apoptosis in response to tetrahydrobiopterin-induced oxidative stress and glucose uptake inhibition: Implication for neurodegeneration

Simone Cardaci, Giuseppe Filomeni, Giuseppe Rotilio, Maria R. Ciriolo

Research output: Contribution to journalArticle

Abstract

BH4 (tetrahydrobiopterin) induces neuronal demise via production of ROS (reactive oxygen species). In the present study we investigated the mechanisms of its toxicity and the redox signalling events responsible for the apoptotic commitment in SH-SY5Y neuroblastoma cells and inmouse primary cortical neurons. We identified in p38MAPK/p53 a BH4-responsive pro-apoptotic signalling axis, as demonstrated by the recovery of neuronal viability achieved by gene silencing or pharmacological inhibition of both p38MAPK and p53. BH4-induced oxidative stress was characterized by a decrease in the GSH/GSSG ratio, an increase in protein carbonylation and DNA damage. BH4 toxicity and the redox-activated apoptotic pathway were counteracted by the H2O2-scavengers catalase and N-acetylcysteine and enhanced by the GSH neo-synthesis inhibitor BSO (buthionine sulfoximine). We also demonstrated that BH4 impairs glucose uptake and utilization, which was prevented by catalase administration. This effect contributes to the neuronal demise, exacerbating BH4-induced nuclear damage and the activation of the pro-apoptotic p38MAPK/p53 axis. Inhibition of glucose uptake was also observed upon treatment with 6-hydroxydopamine, another redox-cycling molecule, suggesting a common mechanism of action for autooxidizable neurotoxins.

Original languageEnglish
Pages (from-to)439-451
Number of pages13
JournalBiochemical Journal
Volume430
Issue number3
DOIs
Publication statusPublished - Sep 15 2010

Keywords

  • Apoptosis
  • Glucose
  • Glutathione
  • Mitogen-activated protein kinase (MAPK)
  • p53
  • Reactive oxygen species (ROS)

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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