Abstract
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 ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened 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 isolates—including the size of proteinase K–resistant PrPSc, the pattern of cerebral PrPSc deposition, and the conformational stability—were 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.
Highlights
Prions, or proteinaceous infectious particles, are self-propagating protein conformations that cause a variety of fatal neurodegenerative illnesses
Transmission of prions to Tg(M109) mice Because Tg mice that express the I109 allotype of bank vole prion protein (BVPrP) develop age-dependent signs of spontaneous neurologic illness [33], we initially focused our studies on Tg mice expressing the M109 allotype
The following prion isolates were tested: sporadic Creutzfeldt-Jakob disease (sCJD); vCJD; sCJD(MM1) prions passaged in Tg mice expressing the M129 variant of human prion protein (PrP) [Tg(HuPrP) mice]; cattle bovine spongiform encephalopathy (BSE); elk chronic wasting disease (CWD); sheep scrapie isolate SSBP/1; sCJD(MM1) prions passaged in guinea pigs; hamster-adapted scrapie strain Sc237; mouse-adapted scrapie strain RML; mouse-adapted BSE strain 301V [maintained in mice expressing either the PrP-A or PrPB allotype of mouse PrP and denoted 301V(A) and 301V(B), respectively]; meadow voles (MV)-adapted RML; and MV-adapted Sc237 prions
Summary
Proteinaceous infectious particles, are self-propagating protein conformations that cause a variety of fatal neurodegenerative illnesses. Prions composed of the prion protein (PrP) cause Creutzfeldt-Jakob disease (CJD) in humans, scrapie in sheep, chronic wasting disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE) [1,2,3]. In these diseases, cellular PrP (PrPC), which is a glycosylphosphatidylinositol (GPI)-anchored membrane protein, undergoes a conformational conversion into a b-sheet-rich, aggregation-prone isoform, termed PrPSc [4,5]. Distinct strains of prions can be distinguished and classified by the incubation periods upon inoculation of laboratory animals, differences in neuroanatomic target areas and patterns of PrPSc deposition within the brain, and biochemical properties, including the molecular weight of PrP 27–30 [7,8]. It is more appropriate to refer to prion strains as ‘‘isolates’’ if they have not been serially passaged
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