Normal host prion protein necessary for scrapie-induced neurotoxicity

Abstract

ACCUMULATION of the prion protein PrP^Sc, a pathological and protease-resistant isoform of the normal host protein PrP^c, is a feature of prion disease such as scrapie^1,2. It is still unknown whether scrapie pathology comes about by neurotoxicity of PrP^Sc, acute depletion of PrP^c, or some other mechanism. Here we investigate this question by grafting neural tissue overexpressing PrP^c into the brain of PrP-deficient mice which are scrapie-resistant and do not propagate infectivity^3–5. After intracerebral inoculation with scrapie prions, the grafts accumulated high levels of PrP^Sc and infectivity and developed the severe histopathological changes characteristic of scrapie. Moreover, substantial amounts of graft-derived PrP^Sc migrated into the host brain. Even 16 months after inoculation no pathological changes were seen in PrP-deficient tissue, not even in the immediate vicinity of the grafts. Therefore, in addition to being resistant to scrapie infection, brain tissue devoid of PrP^c is not damaged by exogenous PrP^Sc.