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(American Journal of Pathology. 1999;155:1723-1730.)
© 1999 American Society for Investigative Pathology

Regular Articles

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

Anthony R. White^*, Steven J. Collins^*, Fran Maher^*, Michael F. Jobling^*, Leanne R. Stewart^*, James M. Thyer^*, Konrad Beyreuther, Colin L. Masters^* and Roberto Cappai^*

From the Department of Pathology,^*
University of Melbourne, Melbourne, Australia; the Mental Health Research Institute,
Parkville, Victoria, Australia; and the Center for Molecular Biology,
University of Heidelberg, Heidelberg, Germany

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrP^c) may be involved in copper homeostasis and modulation of copper/zinc superoxide dismutase (Cu/ZnSOD) activity in neurons. Hydrogen 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 determine whether PrP expression affects neuronal resistance to H₂O₂, we exposed primary cerebellar granule neuron cultures derived from PrP knockout (PrP^-/-) and wild-type (WT) mice to H₂O₂ for 3, 6, and 24 hours. The PrP^-/- neurons were significantly more susceptible to H₂O₂ toxicity than WT neurons after 6 and 24 hours’ exposure. The increased H₂O₂ toxicity may be related to a significant decrease in glutathione reductase activity measured in PrP^-/- neurons both in vitro and in vivo. This was supported by the finding that inhibition of GR activity with 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) increased H₂O₂ toxicity in WT neurons over the same exposure period. The PrP toxic peptide PrP106–126 significantly reduced neuronal glutathione reductase activity and increased susceptibility to H₂O₂ toxicity in neuronal cultures suggesting that PrP toxicity in vivo may involve altered glutathione reductase activity. Our results suggest the pathophysiology of prion diseases may involve perturbed PrP^c function with increased vulnerability to peroxidative stress.

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