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Science 9 November 2007:
Vol. 318. no. 5852, pp. 930 - 936
DOI: 10.1126/science.1138718
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Review
A General Model of Prion Strains and Their Pathogenicity
John Collinge* and
Anthony R. Clarke
MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
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Fig. 1. Propagation of prion strains. (A) Prion propagation proceeds by recruitment of PrP monomers onto a preexisting PrP polymer template followed by fission to generate more templates in an autocatalytic manner. Distinct PrP polymer types can propagate, accounting for different strains. (B) Strains can be differentiated by characteristic incubation periods (length of arrow) and neuropathology (shaded brain area) when inoculated into defined inbred mice. Strain-specific PrPSc fragment patterns following proteolysis are illustrated in diagrammatic Western blots (vertical bars). Both biological and biochemical strain characteristics are closely maintained on serial passage in the same host expressing the same PrPC. (C) Properties of a single strain may be retained after passage in a range of different species with distinct PrPC sequences, when re-isolated in the original host.
[View Larger Version of this Image (45K GIF file)]
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Fig. 2. (A) Conformational selection and transmission barriers. A wide range of mammalian PrPSc conformations are possible, but only a subset is compatible with each individual PrP primary structure. Ease of transmission of prions between species relates to overlap of permissible PrPSc conformations between PrP primary structures from the two species. Though represented as clones, prion strains may consist of an ensemble of molecules, and transmission barriers will relate to overlap of these populations. (B) Strain mutation. Illustration of strains as an ensemble of PrPSc molecules or a clone. Strains "breed true" when propagated in host that preferentially propagates the dominant PrPSc type (host A) but may change in a different host (B) that selectively propagates a minor component of the PrPSc ensemble, resulting in apparent strain mutation. Alternatively, with a clonal strain, inoculation into a host (B) expressing PrP with a sequence incompatible with this PrPSc conformation would only result in transmission by direct strain mutation. These alternatives are not mutually exclusive. It is possible that strain selection and mutation may occur in different tissues of the same host as well as between different hosts as a result of heterogeneity in cellular mechanisms affecting prion propagation and clearance kinetics.
[View Larger Version of this Image (34K GIF file)]
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Fig. 3. Toxicity and prion titer. According to the proposed models illustrated in Fig. 4, toxicity is due to the buildup of a templated intermediate or side-product, PrPL, while the infectious agent itself is not directly toxic. This graph illustrates (in a highly schematic form) the separation of the two phenomena. Prion titer is shown in black and PrPL concentration in red (86). Vertical dotted lines indicate time of onset of clinical signs and death. Green-shaded area denotes a level of PrPL that can be tolerated without clinical symptoms. The upper, pink-shaded region represents a level of PrPL that causes clinical illness; both titer and toxicity lines terminate at death of the animal. The incubation period is thus the time taken for PrPL levels to cross the boundary. Four host/strain combinations are exemplified: tga20 mice express PrPC at  10-fold above levels seen in wild-type mice, whereas Prnpo/+ mice express at 50% of wild-type levels. The effect of PrPC expression level on infection with mouse prions (RML strain) is demonstrated by the first three examples, whereas the fourth indicates wild-type mice infected with hamster (Sc237 strain) prions where prions propagate to high levels but without clinical onset during a normal life span (subclinical infection).
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Fig. 4. Illustrative models for production of PrPL:(A) Toxic templated intermediate. The most rudimentary model has four steps: binding, initial conversion, maturation, and fission. It is possible that PrPL must dissociate before it is toxic, but this is not a prerequisite. The number of PrPC molecules (n) joining, converting, and maturing per cycle does not affect the qualitative behavior of the model. (B) Toxic templated side product. In this model, PrPSc acts as surface catalyst for the conversion of PrPC to PrPL, but the latter is not an intermediate in the synthesis of PrPSc.
[View Larger Version of this Image (31K GIF file)]
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