Abstract
Host prion (PrPC) genotype is a major determinant for the susceptibility to prion diseases. The Q/K222-PrPC polymorphic variant provides goats and mice with high resistance against classical scrapie and bovine spongiform encephalopathy (BSE); yet its effect against atypical scrapie is unknown. Here, transgenic mice expressing the goat wild-type (wt) or the K222-PrPC variant were intracerebrally inoculated with several natural cases of atypical scrapie from sheep and goat and their susceptibility to the prion disease was determined. Goat wt and K222-PrPC transgenic mice were 100% susceptible to all the atypical scrapie isolates, showing similar survival times and almost identical disease phenotypes. The capacity of the K222-PrPC variant to replicate specifically the atypical scrapie strain as efficiently as the goat wt PrPC, but not the classical scrapie or cattle-BSE as previously reported, further suggests the involvement of concrete areas of the host PrPC in the strain-dependent replication of prions.
Highlights
Scrapie is a fatal neurodegenerative disease of sheep and goats caused by the conversion of the host cellular prion protein (PrPC) into a pathological misfolded form (PrPSc)
NEIKERc IZSTOd INIAVe scrapie (Table 1) and their susceptibilities assessed and compared following previously described methods [5]. Both Q222-Tg501 and K222-Tg516 mice succumbed to the inoculation of all atypical scrapie isolates with 100% attack rates (Table 2)
Intracerebral inoculations of prions in transgenic mice expressing different PRNP polymorphic variants are highly valuable to point to a specific amino acid substitution as the unique mutation responsible for the resistance/susceptibility of a species to a prion disease
Summary
Scrapie is a fatal neurodegenerative disease of sheep and goats caused by the conversion of the host cellular prion protein (PrPC) into a pathological misfolded form (PrPSc). Scrapie occurs in a variety of phenotypes within two forms—classical and atypical scrapie forms—which differ in their incubation periods, clinical signs, neuropathological lesion profiles and/or PrPSc biochemical properties. Susceptibility of sheep and goats to scrapie is strongly determined by the PrPc encoding gene (Prnp) and the prion strain. Strategies to promote breeding for the Prnp allele linked to classical scrapie resistance, A136R154R171, in sheep herds were implemented in some. European countries and in the USA, resulting in rapid decline of classical scrapie outbreaks [3]. A136R154R171 genotype does not provide resistance towards atypical scrapie [4]
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