Novel differences between two human prion strains revealed by two-dimensional gel electrophoresis

The phenotype of human sporadic prion diseases is affected by patient genot ype at codon 129 of the prion protein (PrP) gene, the site of a common meth ionine/valine polymorphism, and by the type of the scrapie PrP (PrPSc), whi ch likely reflects the prion strain. However, two distinct disease phenotyp es, identified as sporadic Creutzfeldt-Jakob disease (M/M2 sCJD) and sporad ic fatal insomnia (sFI), share methionine homozygosity at codon 129 and PrP Sc type 2. One-dimensional gel electrophoresis and immunoblotting reveal no difference between the M/M2 sCJD and sFI species of PrPSc in gel mobility and glycoform ratio. In contrast, the two-dimensional immunoblot demonstrat es that in M/M2 sCJD the full-length PrPSc form is overrepresented and carr ies glycans that are different from those present in the PrPSc of sFI. Beca use the altered glycans are detectable only in the PrPSc and not in the nor mal or cellular PrP (PrPC), they are likely to result from preferential con version to PrPSc of rare PrPC glycoforms. This is the first evidence that a qualitative difference in glycans contributes to prion diversity.