Association of an 11–12 kDa protease-resistant prion protein fragment with subtypes of dura graft-associated Creutzfeldt–Jakob disease and other prion diseases

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Abstract
Creutzfeldt–Jakob disease can develop in subjects given a cadaveric dura mater graft (dCJD). This disease has a phenotypic heterogeneity despite the lack of genetic variation. Numerous plaque-type prion protein (PrP) deposits are found in the brain of some but not all subjects; hence, there may be two subtypes of this clinical entity. To validate dCJD subtypes further, we carried out a larger-scale clinicopathological analysis and typing of protease-resistant PrP (PrPSc) in dCJD cases. Cases with plaque-type PrP deposits (p-dCJD) were shown to be distinct from those without PrP plaques (np-dCJD), from several clinicopathological aspects. Analysis of PrPSc revealed that, while the major PrPSc species from both subtypes was of 21 kDa after deglycosylation (type 1 PrPSc), a C-terminal PrP fragment of 11–12 kDa (fPrP11–12) was associated with np-dCJD but not with p-dCJD. The disease type-specific association of fPrP11–12 was also observed in subjects with other prion diseases. An fPrP11–12-like C-terminal PrP fragment was detected in brain lysates from patients associated with fPrP11–12, but not from patients or normal subjects unassociated with fPrP11–12. Results indicated that fPrP was produced by CJD-associated processes in vivo. The present data provide several lines of evidence that support the need for subtyping of dCJD and contribute to the understanding of the processing of disease-specific PrP species. The unique relationship of fPrP11–12 with CJD phenotype supports the view that the phenotypic heterogeneity of CJD is related to the formation of different types of disease-specific PrP and fragments thereof.