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Variably protease sensitive prionopathy (VPSPr) is a recently described, sporadic human prion disease that is pathologically and biochemically distinct from the currently recognised sporadic Creutzfeldt-Jakob disease (sCJD) subtypes. The defining biochemical features of the abnormal form of the prion protein (PrP Sc ) in VPSPr are increased sensitivity to proteolysis and the presence of an N- and C-terminally cleaved ~8 kDa protease resistant PrP Sc  (PrP res ) fragment. The biochemical and neuropathological profile of VPSPr has been proposed to resemble either Gerstmann–Sträussler–Scheinker syndrome (GSS) or familial CJD with the  PRNP -V180I mutation. However, in some cases of VPSPr two protease resistant bands have been observed in Western blots that co-migrate with those of type 2 PrP res , suggesting that a proportion of the PrP Sc  present in VPSPr has properties similar to those of sCJD.    Results  Here, we have used conformation dependent immunoassay to confirm the presence of PrP Sc  in VPSPr that is more protease sensitive compared with sCJD. However, CDI also shows that a proportion of PrP Sc  in VPSPr resists PK digestion of its C-terminus, distinguishing it from GSS associated with ~8 kDa PrP res , and showing similarity to sCJD. Intensive investigation of a single VPSPr case with frozen tissue from multiple brain regions shows a broad, region-specific spectrum of protease sensitivity and differential stability of PrP Sc  in the absence of PK treatment. Finally, using protein misfolding cyclic amplification and real-time quaking induced conversion, we show that VPSPr PrP Sc  has the potential to seed conversion  in vitro  and that seeding activity is dispersed through a broad range of aggregate sizes. We further propose that seeding activity is associated with the ~19 and ~23 kDa PrP res  rather than the ~8 kDa fragment.    Conclusions  Therefore, PrP Sc  in VPSPr is heterogeneous in terms of protease sensitivity and stability to denaturation with the chaotrope GdnHCl and includes a proportion with similar properties to that found in sCJD.    Electronic supplementary material  The online version of this article (doi:10.1186/s40478-014-0152-4) contains supplementary material, which is available to authorized users.

acta neuropathologica communications

The prion protein protease sensitivity, stability and seeding activity in variably protease sensitive prionopathy brain tissue suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease