Prion Protein-Deficient Neurons Reveal Lower Glutathione Reductase Activity and Increased Susceptibility to Hydrogen Peroxide Toxicity

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encepha-lopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrPc) may be involved in copper homeostasis and modulation of copper/zinc superox-ide dismutase (Cu/ZnSOD) activity in neurons. Hydro-gen peroxide (H2O2) is a toxic reactive oxygen species generated through normal cellular respiration, and neurons contain two important peroxide detoxifying systems (glutathione pathway and catalase). To deter-mine whether PrP expression affects neuronal resis-tance to H2O2, we exposed primary cerebellar gran-ule neuron cultures derived from PrP knockout (PrP2/2) and wild-type (WT) mice to H2O2 for 3, 6, and 24 hours. The PrP2/2 neurons were significantl