NORMAL HOST PRION PROTEIN NECESSARY FOR SCRAPIE-INDUCED NEUROTOXICITY

ACCUMULATION of the prion protein PrPSc, a pathological and protease-r esistant isoform of the normal host protein PrPC, is a feature of prio n disease such as scrapie(1,2). It is still unknown whether scrapie pa thology comes about by neurotoxicity of PrPSc, acute depletion of PrPC , or some other mechanism. Here we investigate this question by grafti ng neural tissue overexpressing PrPC into the brain of PrP-deficient m ice which are scrapie-resistant and do not propagate infectivity(3-5). After intracerebral inoculation with scrapie prions, the grafts accum ulated high levels of PrPSc and infectivity and developed the severe h istopathological changes characteristic of scrapie. Moreover, substant ial amounts of graft-derived PrPSc migrated into the host brain. Even 16 months after inoculation no pathological changes were seen in PrP-d eficient tissue, not even in the immediate vicinity of the grafts. The refore, in addition to being resistant to scrapie infection, brain tis sue devoid of PrPC is not damaged by exogenous PrPSc.