NORMAL HOST PRION PROTEIN (PRPC) IS REQUIRED FOR SCRAPIE SPREAD WITHIN THE CENTRAL-NERVOUS-SYSTEM

Mice devoid of PrPC (Prnp(o/o)) are resistant to scrapie and do not al low propagation of the infectious agent (prion). PrPC-expressing neuro ectodermal tissue grafted into Prnp(o/o) brains but not the surroundin g tissue consistently exhibits scrapie-specific pathology and allows p rion replication after inoculation. Scrapie prions administered intrao cularly into wild-type mice spread efficiently to the central nervous system within 16 weeks. To determine whether PrPC is required for scra pie spread, we inoculated prions intraocularly into Prnp(o/o) mice con taining a PrP-overexpressing neurograft. Neither encephalopathy nor pr otease-resistant PrP (PrPSc) were detected in the grafts for up to 66 weeks, Because grafted PrP-expressing cells elicited an immune respons e that might have interfered with prion spread, me generated Prnp(o/o) mice immunotolerant to PrP and engrafted them with PrP-producing neur oectodermal tissue, Again, intraocular inoculation did not lead to dis ease in the PrP-producing graft. These results demonstrate that PrP is necessary for prion spread along neural pathways.