Coexistence of Both PrPSc Type 1 and 2 in sCJD: Does it Affect the Phenotype?

In sporadic Creutzfeldt-Jakob disease (sCJD) five phenotypically distinct subtypes have been identified based on the methionine (M)/valine (V) polymorphic genotype of codon 129 and two PK-resistant scrapie prion protein (PrPSc) types, which migrate in gel to either 21 kDa (PrPSc type 1) or 19 kDa (PrPSc type 2). sCJD is characterized by phenotypic heterogeneity. The co-existence of both PrPSc types has recently been reported and may complicate the diagnosis. In the present study we analyze the distribution of the two PrPSc types in various brain areas as well as the PrPSc resistance to PK digestion using a rigorous procedure according to Notari et al [Human PrPSc “Typing” pitfalls associated with the use of type 1 selective antibodies combined with relative inefficient hydrolysis of PrPSc by proteinase K, poster presentation, NeuroPrion 2006, Torino], with the intent of assessing the co-occurrence of fully PK-resistant PrPSc types 1 and 2 in a ratio of 50:50 or 60:40 while ascertaining that intermediate fragments are completely digested. We are studying the effect of the co-existence of the two PrPSc types, which occurs in either the same or different brain regions, on the sCJD disease phenotype by examining clinical history and neuropathological changes.