Evidence That Bank Vole PrP Is a Universal Acceptor for Prions

Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP), we inoculated Tg(M109) and Tg(I109) mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109) and Tg(I109) mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD) subtype MM1, into Tg(M109) mice gave incubation periods of approximate to 200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of approximate to 250 days, which shortened to approximate to 150 days upon second passage in Tg(M109) mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109) mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolatesincluding the size of proteinase K-resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stabilitywere remarkably conserved upon serial passage in Tg(M109) mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions. Author Summary Prions are infectious proteins that cause devastating neurodegenerative diseases in both humans and animals. Unlike other rodents, bank voles are highly susceptible to prions from many different species, suggesting that bank voles do not impose a species barrier, which normally restricts the transmission of prions from one species to another. We were curious as to whether the unprecedented promiscuity of bank voles for prions is due to the specific prion protein sequence expressed, or to some other factor inherent to bank vole physiology. To answer this question, we inoculated transgenic mice that express bank vole prion protein [Tg(BVPrP) mice] with a diverse set of prions deriving from eight different species. Like bank voles, Tg(BVPrP) mice were highly susceptible to prions from all species tested, demonstrating that the BVPrP sequence mediates the enhanced susceptibility of bank voles to prions. Because the amino acid sequences of mouse and BVPrP differ at only eight positions, our results demonstrate that alterations to a small subset of residues within PrP can have a profound effect on the susceptibility of an organism to prions from another species.