Why would copper associated with the prion protein at the synapse be of any benefit? Since 1996, there has been increasing evidence that the prion protein increases cellular resistance to oxidative stress (64). Cerebellar neurones and astrocytes from PrPC knockout mice are more sensitive to superoxide toxicity (32,34). Additionally, there is evidence from cell culture models that toxicity of PrPSc involves oxidative stress, as blocking toxicity of the neurotoxic peptide mimic of PrPSc can be achieved with antioxidants (65). Cultured cells "infected" with PrPSc are also much more sensitive to oxidative assault than noninfected cells (66). Our laboratory also has evidence that when N2A neuro-blastoma cells are transfected to overexpress PrPSc they show increased resistance to the toxicity of superoxide. However, when those cells are infected so that they express large amounts of PrPSc instead they are more sensitive to superoxide toxicity (Fig. 3). More recently, there is evidence that PrPC itself is upregulated in prion disease and possibly other diseases marked by the presence of oxidative damage (38).
Not only are neurones lacking PrPC expression more sensitive to oxidative stress, but the same PrPC-deficient neurones are also more sensitive to copper toxicity (33). PC12 cell lines developed to be more resistant to copper toxicity are more resistant to oxidative stress and show increased expression of PrPC (65). A peptide based on the octameric-repeat region of PrPC can block both toxicity caused by either oxidative stress or exogenous copper (33). Oxidative stress and copper toxicity are linked together by the complexity of Fenton chemistry in that copper can catalyze the interconversion of various reactive oxygen species or generate the hydoxyl radical directly from water. Thus, sequestering copper has immediate protective benefits for cells very sensitive to oxidative damage.
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