title: Scrapie susceptibility-linked polymorphisms modulate the in vitro conversion of sheep prion protein to protease-resistant forms.
abstract: Prion diseases are natural transmissible neurodegenerative disorders in humans and animals. They are characterized by the accumulation of a protease-resistant scrapie-associated prion protein (PrPSc) of the host-encoded cellular prion protein (PrPC) mainly in the central nervous system. Polymorphisms in the PrP gene are linked to differences in susceptibility for prion diseases. The mechanisms underlying these effects are still unknown. Here we describe studies of the influence of sheep PrP polymorphisms on the conversion of PrPC into protease-resistant forms. In a cell-free system, sheep PrPSc induced the conversion of sheep PrPC into protease-resistant PrP (PrP-res) similar or identical to PrPSc. Polymorphisms present in either PrPC or PrPSc had dramatic effects on the cell-free conversion efficiencies. The PrP variant associated with a high susceptibility to scrapie and short survival times of scrapie-affected sheep was efficiently converted into PrP-res. The wild-type PrP variant associated with a neutral effect on susceptibility and intermediate survival times was converted with intermediate efficiency. The PrP variant associated with scrapie resistance and long survival times was poorly converted. Thus the in vitro conversion characteristics of the sheep PrP variants reflect their linkage with scrapie susceptibility and survival times of scrapie-affected sheep. The modulating effect of the polymorphisms in PrPC and PrPSc on the cell-free conversion characteristics suggests that, besides the species barrier, polymorphism barriers play a significant role in the transmissibility of prion diseases.
authors.affiliation: Department of Bacteriology, DLO-Institute for Animal Science and Health, P.O. Box b5 8200 AB Lelystad, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Bossers
authors.lastname: Belt PBGM
authors.forename: G J
authors.initials: GJ
authors.lastname: Raymond
authors.forename: B
authors.initials: B
authors.lastname: Caughey
authors.forename: R
authors.initials: R
authors.lastname: de Vries
authors.forename: M A
authors.initials: MA
authors.lastname: Smits
mesh_terms: D000483:Alleles; D000818:Animals; D001921:Brain / Q000821:virology; D002474:Cell-Free System; D003587:Cytomegalovirus; D004198:Disease Susceptibility; D019286:Endopeptidase K / Q000378:metabolism*; D014644:Genetic Variation; D005822:Genetic Vectors; D005838:Genotype; D006801:Humans; D051379:Mice; D009447:Neuroblastoma; D011110:Polymorphism, Genetic; D011328:Prions / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D012608:Scrapie / Q000235:genetics*; D012756:Sheep; D014407:Tumor Cells, Cultured
chemical_list: D011328:Prions; D011994:Recombinant Proteins; D019286:Endopeptidase K