p38MAPK/p53 signaling 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 (1)

1 Biology

Tetrahydrobiopterin (BH4) induces neuronal demise via production of reactive oxygen species (ROS). Here we investigated the mechanisms of its toxicity and the redox signaling events responsible for the apoptotic commitment in SH-SY5Y neuroblastoma cells and in mouse primary cortical neurons. We identified in p38MAPK/p53 a BH4-responsive pro-apoptotic signaling 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 GSH/GSSG ratio, an increase in protein carbonylation and DNA damages. BH4 toxicity and redox-activated apoptotic pathway were counteracted by the H2O2-scavengers, catalase and N-acetylcysteine and enhanced by the GSH neo-synthesis inhibitor, buthionine sulfoximine (BSO). We also demonstrated that BH4 impairs glucose uptake and utilization that were prevented by catalase administration. This effect contributes to the neuronal demise, exacerbating BH4-induced nuclear damages 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 auto-oxidizable neurotoxins.

Mots clés: Life Sciences

Simone Cardaci, Giuseppe Filomeni, Giuseppe Rotilio, Maria R Ciriolo. p38MAPK/p53 signaling axis mediates neuronal apoptosis in response to tetrahydrobiopterin-induced oxidative stress and glucose uptake inhibition: implication for neurodegeneration. Biochemical Journal, 2010, 430 (3), pp.439-451. ⟨10.1042/BJ20100503⟩. ⟨hal-00512008⟩