IN-SITU FORMATION OF PROTEASE-RESISTANT PRION PROTEIN IN TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY-INFECTED BRAIN-SLICES

The transmissible spongiform encephalopathies (TSEs) comprise a group of fatal neurodegenerative diseases that are characterized by the conv ersion of the normal host cellular prion protein (PrPc), to the abnorm al protease-resistant prion protein isoform (PrP-res). It has been pro posed, though not proven, that the infectious TSE agent consists solel y of PrP-res and that PrP-res-induced conformational conversion of PrP c to additional PrP res represents agent replication. In this study we demonstrate in situ conversion of protease-sensitive PrPc to PrP-res in TSE-infected brain slices. One step in this process is the binding of soluble PrPc to endogenous PrP-res deposits. The newly formed PrP-r es associated with the slices in a pattern that correlated with the pr e-existing brain distribution of PrP-res. Punctate in situ PrP convers ion was observed in brain regions containing PrP-res amyloid plaques, and a more dispersed conversion product was detected in areas containi ng diffuse PrP-res deposits. These studies provide direct evidence tha t PrP-res formation involves the incorporation of soluble PrPc into bo th nonfibrillar and fibrillar PrP-res deposits in TSE-infected Ir,rain . Our findings suggest that the in situ PrP conversion reaction leads to additional polymerization of endogenous PrP-res aggregates and is a nalogous to the process of PrP-res fibril and subfibril growth in vivo .