Normal host prion protein (PrP(C)) is required for scrapie spread within the central nervous system

Mice devoid of PrP(C) (Prnp(o/o)) are resistant to scrapie and do not allow propagation of the infectious agent (prion). PrP(C)-expressing neuroectodermal tissue grafted into Prnp(o/o) brains but not the surrounding tissue consistently exhibits scrapie-specific pathology and allows prion replication after inoculation. Scrapie prions administered intraocularly into wild-type mice spread efficiently to the central nervous system within 16 weeks. To determine whether PrP(C) is required for scrapie spread, we inoculated prions intraocularly into Prnp(o/o) mice containing a PrP-overexpressing neurograft. Neither encephalopathy nor protease-resistant PrP (PrP(Sc)) were detected in the grafts for up to 66 weeks. Because grafted PrP-expressing cells elicited an immune response that might have interfered with prion spread, we generated Prnp(o/o) mice immunotolerant to PrP and engrafted them with PrP-producing neuroectodermal tissue. Again, intraocular inoculation did not lead to disease in the PrP-producing graft. These results demonstrate that PrP is necessary for prion spread along neural pathways.