Scientific Commentary |
Sporadic Creutzfeldt–Jakob disease: further twists and turns in a convoluted protein
Sporadic Creutzfeldt–Jakob disease (sCJD) is the commonest form of human prion disease, with an annual mortality rate of
1–1.5 million cases per annum in most countries where systematic surveillance has been established (Ladogana et al., 2005
). The combined data from these studies have allowed analysis of hundreds of cases of this rare disease, as shown by Collins and colleagues, in this issue of Brain (Collins et al., 2006). The phenotypic spectrum of sCJD is broad, including several clinical subgroups that have been recognized for many years, amongst which are the Brownell–Oppenheimer and Heidenhain variants. The basis of this clinicopathological variation in sCJD has been studied for over 10 years, with the general consensus that the two major phenotypic determinants are the presence of either methionine or valine at the polymorphic codon 129 of the patient's prion protein gene (PRNP), and the physico-chemical properties of the abnormal prion protein (PrPSc) that accumulates in the brain during the course of the disease (Ironside et al., 2005). The former is readily and unambiguously determined by restriction length polymorphism analysis or gene sequencing, but the latter is generally approached indirectly by determining the size of the protease resistant core fragment of the PrPSc by western blotting of detergent-extracted and proteinase K-digested homogenates of CJD brain tissue.
Two rival classification systems for the PrPSc isoforms accumulating in the brain in sCJD and other human prion disorders exist (Parchi et al., 1999, Hill et al., 2003). Although much has been made of their differences, a neutral observer would be struck by the considerable extent of overlap between the two systems. The Hill et al. (2003) system recognizes three PrPSc size classes, whereas two major classes (with subtypes) are recognized by Parchi et al. (1999). However, not all possible codon 129 genotype/PrPSc type combinations occur in the Hill classification, whereas Parchi et al. recognize all six potential genotype/isotype combinations in their classification (MM1, MM2, MV1, MV2, VV1 and VV2), with two phenotypes for the MM2 subgroup (sCJD and sporadic fatal insomnia, depending at least in part on differences in PrPSc glycosylation) (Pan et al. 2001). A reasonable assumption would be that the Hill et al. (2003) types 1 and 2 correspond to the Parchi et al. type 1, and that the Hill et al. type 3 is the Parchi et al. (1999) type 2. Given that Hill et al. (2003) report their type 1 PrPSc to occur solely in codon 129 methionine homozygotes, this group would be expected to constitute a subset of the MM1 group of Parchi et al. (1999). In effect, these differences may hinge on methodological issues used for PrPSc analysis and the existence of a minor phenotypic subgroup.
In their paper, in this issue of Brain, Cali et al. (2006) re-examine this issue by selecting a cohort of Parchi et al. (1999) sCJD MM1 cases and segregating them by disease duration, assuming these to comprise Hill et al. (2003) 1MM and 2MM cases. They go on to show that there is no statistically significant difference between these two groups in clinical findings, pathological phenotype or biochemical properties of PrPSc. Instead, they point to the effects of pH variation in introducing microheterogeneity in the extent of N-terminal truncation of PrPSc (Notari et al., 2004) as an explanation for the artefactual (in their view) subdivision of the single MM1 Parchi et al. (1999) subgroup. It is tempting to suggest that these results go a long way to squaring this particular circle, and that what remains is a question of nomenclature rather than an issue of disease classification; however this is not so. Irrespective of whether these two rival PrPSc classification systems are compatible, neither has, as yet, dealt with the issue of cases of sCJD in which more than one PrPSc type is present.
The first report of this phenomenon was, in fact, contained in Parchi et al. (1999); however, it rapidly became clear that the proportion of sCJD cases that could be shown to contain two PrPSc types is a function of the extent of the brain sampling protocol employed (Puoti et al., 1999; Head et al., 2004; Schoch et al., 2006). Moreover, once sufficiently discriminatory tools are employed, it has been shown in two independent laboratories that all cases previously classified as type 2 (Parchi et al., 1999) can in addition be shown to contain normally sub-detectable levels of type 1 PrPSc (Polymenidou et al., 2005, Yull et al., 2006; Fig. 1). How can these findings illuminate the proposed links between PrPSc isoform, PRNP codon 129 polymorphisms and the resulting spectrum of disease phenotype in humans?
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On the basis of these results it is likely that any study focusing on a single sCJD subtype, such as that reported in a detailed clinical study of the sCJD MV2 subgroup in this issue of Brain, Krasnianski et al. (2006)
is likely to be dealing with cases that are heterogeneous in terms of the actual PrPSc types present in the brain as a whole. An example of the detection of type 1 PrPSc within a single brain region in a sCJD ‘MV2 case’ is shown in Fig. 2. Might this explain some of the obvious phenotypic heterogeneity between cases of the same sCJD subgroup and the apparent phenotypic overlap between different sCJD subgroups? Detailed neuropathological analysis by Puoti et al. (1999), has previously shown that the presence of either type 1 or type 2 PrPSc in the same sCJD brain has regional pathological correlates. However, no clinical correlates were offered (Puoti et al., 1999). It now appears that when very large cohorts of sCJD cases are analysed, as described by Collins et al. (2006) in this issue of Brain, the minority of cases classified as containing both type 1 and type 2 tend to display a phenotype distinct from those classified as containing only one type. The authors tentatively suggest that these cases with mixed PrPSc types may represent a third phenotype within each of the three codon 129 genotypic groups (Collins et al., 2006).
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If consensus on the molecular classification of sCJD has proved difficult to reach in the past, then the integration of these recent findings can only further complicate matters in the short term. In the longer term, the biological significance of these differences in PrPSc classification requires further exploration by experimental transmission, which allows the identification of different biological strains of the prion agent, each of which should (if PrPSc isotype analysis is equivalent to ‘molecular’ strain typing) correspond to different PrPSc isotypes (Clarke et al., 2001
). However, these experiments are costly, complicated, lengthy and require considerable planning in terms of the experimental approach and the animal models to be used. Biological strain typing was defined on the basis of transmission characteristics (particularly disease incubation period and the pattern of vacuolation in the brain) following intracerebral inoculation in inbred groups of mice, and the use of ‘humanized’ transgenic mice, particularly those which overexpress the transgene, does not constitute a directly comparable approach (Bruce, 2003).
An alternative approach would be to employ techniques that more directly address the relevant conformational differences of PrPSc within the brain in prion diseases, such as a technique known as conformation-dependent immunoassay (CDI). This technique does not rely on the use of proteinase K for specificity for PrPSc, but instead uses guanidine denaturation to produce a ‘melt curve’ for different isoforms of prion protein, employing specific antibodies to recognize different epitopes on the prion protein exposed by the denaturation process (Safar et al., 1988). CDI is claimed to be highly sensitive (Safar et al., 2002) and has been used to identify different strains of experimental prion diseases in rodents (Safar et al., 1988). Whether this approach can also be used to recognize multiple PrPSc species in the brain in human prion diseases, or different strains of human prion disease are important possibilities that require further exploration. At present, the identification of a minority or even a majority of sCJD cases containing multiple PrPSc types (which can only be established by detailed and thorough neuropathological and biochemical examinations) appears to offer an explanation for at least part of the phenotypic heterogeneity in sCJD.
National Creutzfeldt-Jakob disease Surveillance Unit, University of Edinburgh, Western General Hospital Edinburgh EH4 2 XU, UK
E-mail: james.ironside{at}ed.ac.uk
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Acknowledgements |
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The National Creutzfeldt–Jakob disease Surveillance Unit is supported by the Department of Health and the Scottish Executive.
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