Non-genetic propagation of strain-specific properties of scrapie prion protein.
The infectious agents causing scrapie and other transmissible spongiform encephalopathies have been postulated to consist solely of the protease-resistant form of prion protein (PrPSc). One unprecedented requirement of the protein-only model is that the 'inheritance' of pathogen strain differences must be mediated by stable variations in PrPSc structure, rather than mutations in an agent-specific nucleic acid. Strain differences in PrPSc structure have been described for the hyper (HY) and drowsy (DY) strains of hamster transmissible mink encephalopathy (TME), a scrapie-like disease originating in mink. Although HY and DY PrPSc are both post-translationally derived from the precursor prion protein (PrPC) they are cleaved at different amino-terminal sites by proteinase K (ref. 8). Here we investigate whether this strain-specific property of PrPSc is transmitted to PrPC during formation of new PrPSc. PrPSc from the HY and DY TME strains converted the protease-sensitive PrPC into two distinct sets of protease-resistant PrP products in a cell-free system. These data provide evidence that self-propagation of PrPSc polymers with distinct three-dimensional structures could be the molecular basis of scrapie strains.
Bessen
R A
RA
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA.
Kocisko
D A
DA
Raymond
G J
GJ
Nandan
S
S
Lansbury
P T
PT
Caughey
B
B
D000818:Animals; D002594:Cetylpyridinium / Q000494:pharmacology; D006224:Cricetinae; D046508:Culture Techniques; D019286:Endopeptidase K; D019791:Guanidine; D006146:Guanidines / Q000494:pharmacology; D008647:Mesocricetus; D018621:PrPC Proteins / Q000737:chemistry / Q000378:metabolism*; D018620:PrPSc Proteins / Q000737:chemistry / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000145:classification / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D013045:Species Specificity
D006146:Guanidines; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; D002594:Cetylpyridinium; D012697:Serine Endopeptidases; D019286:Endopeptidase K; D019791:Guanidine