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Non-genetic propagation of strain-specific properties of scrapie prion protein
R A Bessen1, D A Kocisko, G J Raymond
1Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, Hamilton, Montana 59840, USA.
Abstract:
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.
Insights
The infectious agents causing transmissible spongiform encephalopathies, like scrapie, may be protein-only. This study shows that prion protein structure variations can explain disease strain differences, supporting the protein-only hypothesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Infectious Diseases
Background:
- Transmissible spongiform encephalopathies (TSEs) are linked to the protease-resistant prion protein (PrPSc).
- The protein-only hypothesis requires PrPSc structural variations to explain pathogen strain differences, as opposed to nucleic acid mutations.
- Distinct structural variations in PrPSc have been observed between hyper (HY) and drowsy (DY) strains of transmissible mink encephalopathy (TME).
Purpose of the Study:
- To investigate if strain-specific PrPSc properties are transmitted to the precursor prion protein (PrPC) during de novo PrPSc formation.
- To determine the molecular basis of scrapie strain diversity.
Main Methods:
- Utilized a cell-free system to study the conversion of protease-sensitive PrPC to protease-resistant PrPSc.
- Compared the conversion products of HY and DY TME strains of PrPSc.
Main Results:
- PrPSc from HY and DY TME strains successfully converted PrPC into two distinct sets of protease-resistant PrP products.
- Demonstrated that strain-specific cleavage patterns of PrPSc by proteinase K are maintained during conversion.
Conclusions:
- The self-propagation of PrPSc polymers with distinct three-dimensional structures provides strong evidence for the molecular basis of scrapie strains.
- Supports the protein-only hypothesis for the origin and diversity of TSEs.