Novel Differences between Two Human Prion Strains Revealed by Two-dimensional Gel Electrophoresis

The phenotype of human sporadic prion diseases is affected by patient genotype at codon 129 of the prion protein (PrP) gene, the site of a common methionine/valine polymorphism, and by the type of the scrapie PrP (PrP ^Sc), which likely reflects the prion strain. However, two distinct disease phenotypes, identified as sporadic Creutzfeldt-Jakob disease (M/M2 sCJD) and sporadic 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 PrP^Sc in gel mobility and glycoform ratio. In contrast, the two-dimensional immunoblot demonstrates that in M/M2 sCJD the full-length PrP^Sc form is overrepresented and carries glycans that are different from those present in the PrP^Sc of sFI. Because the altered glycans are detectable only in the PrP^Sc and not in the normal or cellular PrP (PrP^C), they are likely to result from preferential conversion to PrP^Sc of rare PrP^C glycoforms. This is the first evidence that a qualitative difference in glycans contributes to prion diversity.