Revised Manuscript Received October 29, 1992 abstract: The only component of the infectious scrapie prionidentified to date is a protein designated PrPSo. A posttranslational process convertsthe cellular PrP isoform (PrP0) into PrPSc. Denatured PrP® 0 was digested with endoproteases, and the resulting fragments were isolated by HPLC. Byboth mass spectrometry and Edman sequencing, the primary structure of PrP80 was found to be the same as that deduced from the PrP gene sequence, arguing that neither RNA editing nor protein splicing feature in the synthesis of PrP80. Mass spectrometry also was used to search for posttranslationalchemical modifications other than the glycosylinositol phospholipid anchor attached to the C-terminus and two Asn-linked oligosaccharides already known to occur on both PrP80 and PrP. These results contend that PrP80 molecules do not differ from PrPat the level of an amino acid substitution or a posttranslational chemical modification; however, we cannot eliminate the possibilitythat a small fraction of PrPSc is modified by an as yet unidentified posttranslational process or that PrPcarries a modification that is removed in the formation of PrP80. It seems likely that PrP80 differs from PrPin its secondary and tertiary structure, but the possibility of a tightly bound, disease-specific molecule which purifies with PrP80 must also be considered.

Studies designed to assess the molecular composition of the transmissible pathogen causing scrapie by UV and ionizing radiation gave results which ledto the unorthodox suggestion that scrapie agent infectivity might replicate in the absence of a nucleic acid (Alper et al., 1966, 1967, 1978). Reaction to this proposal was mixed, leading, on one hand, to a variety of structural hypotheses about the composition of the infectious