Association of prion protein genotype and scrapie prion protein type with cellular prion protein charge isoform profiles in cerebrospinal fluid of humans with sporadic or familial prion diseases

The present study investigates whether posttranslational modifications of cellular prion protein (PrPC) in the cerebrospinal fluid (CSF) of humans with prion diseases are associated with methionine (M) and/or valine (V) polymorphism at codon 129 of the prion protein gene (PRNP), scrapie prion protein (PrPSc) type in sporadic Creutzfeldt-Jakob disease (sCJD), or PRNP mutations in familial Creutzfeldt-Jakob disease (fCJD/E200K), and fatal familial insomnia (FFI). We performed comparative 2-dimensional immunoblotting of PrPC charge isoforms in CSF samples from cohorts of diseased and control donors. Mean levels of total PrPC were significantly lower in the CSF from fCJD patients than from those with sCJD or FFI. Of the 12 most abundant PrPC isoforms in the examined CSF, one (IF12) was relatively decreased in (1) sCJD with VV (vs. MM or MV) at PRNP codon 129; (2) in sCJD with PrPSc type 2 (vs. PrPSc type 1); and (3) in FFI versus sCJD or fCJD. Furthermore, truncated PrPC species were detected in sCJD and control samples without discernible differences. Finally, serine 43 of PrPC in the CSF and brain tissue from CJD patients showed more pronounced phosphorylation than in control donors.