Copper is toxic to PrP-ablated mice and exacerbates disease in a mouse model of E200K genetic prion disease

The pathogenesis of the diverse forms of prion disease was attributed solely to the accumulation of the misfolded PrP forms, and not to the potential loss of normal PrP ^C function during disease propagation. In this respect, it was also not established whether mutant PrPs linked to genetic prion diseases, as is the case for E200K PrP, preserve the function of PrP ^C. We now show that fibroblasts generated from both PrP-ablated mice and TgMHu2ME199K, a transgenic mouse line mimicking E200KCJD, were significantly more sensitive to copper toxicity than wt fibroblasts. Long-term administration of copper significantly accelerated the onset and progression of spontaneous prion disease in TgMHu2ME199K mice and caused marked irritability and cerebellar associated tip-toe walking in PrP ^0/0 mice, while wt mice were not affected. Our results are consistent with the hypothesis that a functional PrP ^C is required to protect cells from high levels of copper, and that its substitution for a nonfunctional mutant PrP may accelerate the onset of genetic prion disease during oxidative insults.