title: Caprine PrP variants harboring Asp-146, His-154 and Gln-211 alleles display reduced convertibility upon interaction with pathogenic murine prion protein in scrapie infected cells.
abstract: Scrapie, the prion disease of sheep and goats, is a devastating malady of small ruminants. Due to its infectious nature, epidemic outbreaks may occur in flocks/herds consisting of highly susceptible animals. Field studies identified scrapie-protective caprine PrP variants, harboring specific single amino acid changes (Met-142, Arg-143, Asp-146, Ser-146, His-154, Gln-211 and Lys-222). Their effects are under further evaluation, and aim to determine the most protective allele. We assessed some of these variants (Asp-146, His-154, Gln-211 and Lys-222), after their exogenous expression as murine-caprine chimeras in a scrapie- infected murine cell line. We report that exogenously expressed PrPs undergo conformational conversion upon interaction with the endogenous pathological murine prion protein (PrPSC), which results in the detection of goat-specific and partially PK-resistant moieties. These moieties display a PK-resistance pattern distinct from the one detected in natural goat scrapie cases. Within this cellular model, distinct conformational conversion potentials were assigned to the tested variants. Molecules carrying the Asp-146, His-154 and Gln-211 alleles showed significantly lower conversion levels compared to wild type, confirming their protective effects against scrapie. Although we utilized a heterologous conversion system, this is to our knowledge, the first study of caprine PrP variants in a cellular context of scrapie, that confirms the protective effects of some of the studied alleles.
authors.affiliation: a Department of Genetics , Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki , Thessaloniki , Greece.|b School of Pharmacy , Aristotle University of Thessaloniki , Thessaloniki , Greece.
authors.forename: Eirini
authors.initials: E
authors.lastname: Kanata
authors.affiliation: a Department of Genetics , Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki , Thessaloniki , Greece.
authors.forename: Minas
authors.initials: M
authors.lastname: Arsenakis
authors.affiliation: b School of Pharmacy , Aristotle University of Thessaloniki , Thessaloniki , Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Sklaviadis
mesh_terms: D000483:Alleles; D000818:Animals; D001216:Asparagine / Q000235:genetics*; D002460:Cell Line; D005998:Glycine / Q000235:genetics*; D006041:Goats; D006639:Histidine / Q000235:genetics*; D051379:Mice; D000072002:Prion Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D012608:Scrapie / Q000378:metabolism / Q000473:pathology*
chemical_list: D000072002:Prion Proteins; D006639:Histidine; D001216:Asparagine; D005998:Glycine
keywords: 22LN2a#58; Scrapie; cell culture; genotyping; goats; polymorphisms; resistance