Cellular prion protein suppressess the apoptotic cell death by mediating the intracellular H₂O₂ in primary culture and immortalized neuronal cells

Abstract

To know the mechanisms in which cellular isoform of prion protein (PrP^C) is involved for the neuroprotection, we compared death signals in Prnp^-/- primary cultivated neurons to those in wild-type (WT) primary cultivated neurons. These results are also confirmed by immortarized neuronal cells. When copper was exposed to these neurons, the both of type-1 and type-2 Prnp^-/- neurons were more sensitive and underwent apoptotic cell death more readily than WT neurons. The cell death in Prnp^-/- neurons was effectively inhibited by anti-oxidants or some caspase-inhibitors as seen in wild-type neurons. In Prnp^-/- neurons, copper toxicity was enhanced more significantly by deprivation of anti-oxidants, and then induced more increasing apoptotic features. To know the level of the reactive oxygen species, the level of the intracellular hydrogen peroxide (H₂O₂) were measured. Intracellular H₂O₂ in Prnp^-/- cells decreased more rapidly than that in WT cells. These data demonstrate that in Prnp^-/- neurons, copper may be a strong mediator to convert H₂O₂ to more toxic free radicals in a fenton-like reaction, which induces more caspase-mediated apoptosis. These results suggest that PrP^C may moderate the intracellular H₂O₂ level as a copper binding protein or an anti-oxidant to protect neuronal cells from apoptotic death.