Ian Gowland

The same prion strain causes vCJD and BSE

Epidemiological and clinicopathological studies, allied with pathological prion protein (PrPSc) analysis, strongly support the hypothesis that the human prion disease new variant Creutzfeldt-Jakob disease (vCJD) is causally related to bovine spongiform encephalopathy (BSE),, but considerable controversy remains. Distinct prion strains are distinguished by their biological properties on transmission to laboratory animals and by physical and chemical differences in PrPSc strains. We now find that the biological and molecular transmission characteristics of vCJD are consistent with it being the human counterpart of BSE.

Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration

Prion protein (PrP) plays a crucial role in prion disease, but its physiological function remains unclear Mice with gene deletions restricted to the coding region of PrP have only minor phenotypic deficits, but are resistant to prion disease We generated double transgenic mice using the Cre–loxP system to examine the effects of PrP depletion on neuronal survival and function in adult brain Cre‐mediated ablation of PrP in neurons occurred after 9 weeks We found that the mice remained healthy without evidence of neurodegeneration or other histopathological changes for up to 15 months post‐knockout However, on neurophysiological evaluation, they showed significant reduction of afterhyperpolarization potentials (AHPs) in hippocampal CA1 cells, suggesting a direct role for PrP in the modulation of neuronal excitability These data provide new insights into PrP function Furthermore, they show that acute depletion of PrP does not affect neuronal survival in this model, ruling out loss of PrP function as a pathogenic mechanism in prion disease and validating therapeutic approaches targeting PrP.

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

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 PrPSc 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.

Human Prion Protein with Valine 129 Prevents Expression of Variant CJD Phenotype

Variant Creutzfeldt-Jakob disease (vCJD) is a unique and highly distinctive clinicopathological and molecular phenotype of human prion disease associated with infection with bovine spongiform encephalopathy (BSE)–like prions. Here, we found that generation of this phenotype in transgenic mice required expression of human prion protein (PrP) with methionine 129. Expression of human PrP with valine 129 resulted in a distinct phenotype and, remarkably, persistence of a barrier to transmission of BSE-derived prions on subpassage. Polymorphic residue 129 of human PrP dictated propagation of distinct prion strains after BSE prion infection. Thus, primary and secondary human infection with BSE-derived prions may result in sporadic CJD-like or novel phenotypes in addition to vCJD, depending on the genotype of the prion source and the recipient.

Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins.

Approximately 15 % of human prion disease is associated with autosomal-dominant pathogenic mutations in the prion protein (PrP) gene. Previous attempts to model these diseases in mice have expressed human PrP mutations in murine PrP, but this may have different structural consequences. Here, we describe transgenic mice expressing human PrP with P102L or E200K mutations and methionine (M) at the polymorphic residue 129. Although no spontaneous disease developed in aged animals, these mice were readily susceptible to prion infection from patients with the homotypic pathogenic mutation. However, while variant Creutzfeldt–Jakob disease (CJD) prions transmitted infection efficiently to both lines of mice, markedly different susceptibilities to classical (sporadic and iatrogenic) CJD prions were observed. Prions from E200K and classical CJD M129 homozygous patients, transmitted disease with equivalent efficiencies and short incubation periods in human PrP 200K, 129M transgenic mice. However, mismatch at residue 129 between inoculum and host dramatically increased the incubation period. In human PrP 102L, 129M transgenic mice, short disease incubation periods were only observed with transmissions of prions from P102L patients, whereas classical CJD prions showed prolonged and variable incubation periods irrespective of the codon 129 genotype. Analysis of disease-related PrP (PrPSc) showed marked alteration in the PrPSc glycoform ratio propagated after transmission of classical CJD prions, consistent with the PrP point mutations directly influencing PrPSc assembly. These data indicate that P102L or E200K mutations of human PrP have differing effects on prion propagation that depend upon prion strain type and can be significantly influenced by mismatch at the polymorphic residue 129.

Pathogenic human prion protein rescues PrP null phenotype in transgenic mice

Infectious prion diseases may be acquired, sporadic or inherited in their aetiology. Inherited prion diseases are caused by coding mutations in the prion protein (PrP) gene. We investigated whether one of the commonest of these mutations, E200K, results in a functionally inactive prion protein by expressing human PrP 200K in transgenic mice homozygous for murine PrP null alleles. We examined the intrinsic properties of hippocampal CA1 pyramidal cells in these mice by measuring the resting potential, time constants and amplitude of the slow after-hyperpolarisation (AHP). These mice show rescue of the reduced slow AHP electrophysiological phenotype found in PrP null mice. Using the AHP as a marker for PrP function, we conclude that this pathogenic PrP mutation, does not significantly affect the normal neuronal function of PrP.