Defining sporadic Creutzfeldt-Jakob disease strains and their transmission properties

Abstract

The biological determinants of the phenotypic variation in sporadic Creutzfeldt-Jakob disease (sCJD) are unknown. To categorize sCJD cases, the prion protein (PrP) codon 129 genotype and the biochemical characteristics of the disease-associated form of PrP (PrP(Sc)) can be combined to form six subgroups (MM1, MM2, MV1, MV2, VV1, and VV2). This classification largely correlates with the known variation in the clinical and pathological features of sCJD, with the MM1 and MV1 cases representing the "classic" phenotype of sCJD. To address how this classification relates to different strains of sCJD we have inoculated each subgroup of sCJD to a panel of mice expressing different forms of the human PRNP gene (129MM, 129VV, and 129MV). We have established that all subtypes are transmissible to at least one genotype of mouse, and both agent and host factors determine transmission efficiency and the form of PrP(Sc) deposited in the brain. Moreover, we have identified four distinct strains of sCJD using our in vivo strain typing panel.

Fig. 1.

Lesion profile charts of primary passage vacuolation scoring data. The distribution and intensity of TSE-associated vacuolation was assessed for each mouse in the primary inoculation experiments. Mean vacuolation scores for nine gray matter (GM1–GM9) and three white matter (WM1–WM3) brain regions were plotted. Lesion profile data have been grouped horizontally according to the predicted sCJD strain groupings and vertically according to host codon 129 genotype. No data are shown for sCJD(VV1) in HuMM mice and for sCJD(MM2) because no TSE vacuolation was observed. Error bars, ±SEM; mean values based on at least five individual mouse scores; brain regions defined in Materials and Methods.

Fig. 2.

Comparison of immunocytochemistry data from transgenic mice inoculated with six sCJD subgroups. PrP^Sc deposition within the brain was assessed for variation in brain region targeted and morphology of deposits, in the understanding that this may vary according to the sCJD agent strain inoculated and the host codon 129 genotype. Immunocytochemistry with anti-PrP antibody (6H4, brown staining) was performed on histological sections of the mouse brains. Representative sections are shown for coronal sections through the hippocampus/thalamus from primary passage mice. All HuMM mice inoculated with sCJD(MM2) were negative for PrP^Sc deposition. (Magnification: 2.5×.)

Fig. 3.

Secondary passage lesion profiles. For secondary passage experiments of sCJD(MM1), sCJD(MV2), and sCJD(VV2), mean vacuolation scores were plotted. Data shown (mean ± SEM) compare profiles between sCJD subgroups (horizontal panels) against the three host genotypes (vertical panels). Each panel includes the primary passage lesion profile for that data set. Filled circles, primary passage; open triangles, second passage from HuMM inocula; open diamonds, second passage from HuMV inocula; asterisks, second passage from HuVV inocula.