BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein

Abstract

Variant Creutzfeldt-Jakob disease (vCJD) has been recognized to date only in individuals homozygous for methionine at PRNP codon 129. Here we show that transgenic mice expressing human PrP methionine 129, inoculated with either bovine spongiform encephalopathy (BSE) or variant CJD prions, may develop the neuropathological and molecular phenotype of vCJD, consistent with these diseases being caused by the same prion strain. Surprisingly, however, BSE transmission to these transgenic mice, in addition to producing a vCJD-like phenotype, can also result in a distinct molecular phenotype that is indistinguishable from that of sporadic CJD with PrP(Sc) type 2. These data suggest that more than one BSE-derived prion strain might infect humans; it is therefore possible that some patients with a phenotype consistent with sporadic CJD may have a disease arising from BSE exposure.

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study

“…Experimental confirmation that variant CreutzfeldtJakob disease (vCJD) [1] is caused by the same prion strain as that causing bovine spongiform encephalopathy (BSE) in cattle [2][3][4][5] led to global concern that human exposure to BSE prions posed a significant threat to public health [6][7][8]. While the risk of new dietary exposure to BSE prions in the UK is now remote [9], the majority of the UK population may have been exposed during the late 1980s and early 1990s.…”

“…Owing to the paucity of tissue available, it was not possible to inoculate different lines of transgenic mice expressing either human PrP 129 methionine or valine. Based on our experience of the transmission properties of vCJD and BSE prions, we chose to use Tg45 mice homozygous for 129 methionine [5]. These mice faithfully propagate the molecular and neuropathological phenotype of vCJD following primary challenge with either vCJD prions [5,57] or BSE prions [5] and are known to be sensitive to infection when inoculated with vCJD peripheral tissue containing PrP Sc at a concentration 10 4.7 -fold lower than in brain [57].…”

“…Based on our experience of the transmission properties of vCJD and BSE prions, we chose to use Tg45 mice homozygous for 129 methionine [5]. These mice faithfully propagate the molecular and neuropathological phenotype of vCJD following primary challenge with either vCJD prions [5,57] or BSE prions [5] and are known to be sensitive to infection when inoculated with vCJD peripheral tissue containing PrP Sc at a concentration 10 4.7 -fold lower than in brain [57]. Importantly, the novel prion strain (associated with type 5 PrP Sc ) that is generated in vCJD-challenged human PrP 129V transgenic mice also transmits infection efficiently to transgenic mice expressing human PrP 129M [51].…”

Rodent models for prion diseases

“…-mapping PrP regions involved in or required for PrP conversion and prion replication [36,37,44,56,57,63,78,80]; -studies on the physiological role of PrP C and the contributions of individual molecular regions to these functions [65]; -studies on molecular aspects of species barrier effects by mutation of single or limited numbers of positions within the PrP [20,41,51,76,77,82]; -modelling of familial forms of human prion diseases [3,4,60]; -analysis of the cell specificity of prion propagation [48,71,72]; -analysis of the role of PrP glycosylation [22,64]; -studies on the mechanisms of prion spread [11,12]; -studies on the neuropathological roles of PrP C and of PrP D in prion disease [39]; -studies on the function of PrP Doppel [34].…”

“…represented only one defined strain when reisolated from a variety of species (including vCJD in humans) which were infected during the course of the BSE epidemic in the UK. Asante et al [3] have reported that the transmission of BSE to Tg35 mice overexpressing human PrP C produced primarily the well known vCJD PrP D phenotype, but also in low numbers a second phenotype (distinguished by biochemical and anatomical analysis of the PrP D deposits) which was reminiscent of sporadic CJD PrP D . Another publication describes the transmission of a new bovine prion strain called bovine amyloidotic spongiform encephalopathy (BASE), which can be discriminated from BSE mainly on the basis of a lower molecular mass of the unglycosylated form of PrP D , a different anatomical distribution of the accumulated PrP D in the brain, and by the presence of PrP immunoreactive amyloid plaques, bovine PrP transgenic mice.…”