Abstract
Despite their phenotypic heterogeneity, most human prion diseases belong to two broadly defined groups: Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker disease (GSS). While the structural characteristics of the disease-related proteinase K-resistant prion protein (resPrPD) associated with the CJD group are fairly well established, many features of GSS-associated resPrPD are unclear. Electrophoretic profiles of resPrPD associated with GSS variants typically show 6–8 kDa bands corresponding to the internal PrP fragments as well as a variable number of higher molecular weight bands, the molecular nature of which has not been investigated. Here we have performed systematic studies of purified resPrPD species extracted from GSS cases with the A117V (GSSA117V) and F198S (GSSF198S) PrP gene mutations. The combined analysis based on epitope mapping, deglycosylation treatment and direct amino acid sequencing by mass spectrometry provided a conclusive evidence that high molecular weight resPrPD species seen in electrophoretic profiles represent covalently-linked multimers of the internal ~ 7 and ~ 8 kDa fragments. This finding reveals a mechanism of resPrPD aggregate formation that has not been previously established in prion diseases.
Highlights
A well-known feature of human prion diseases is the presence of three distinct etiologic forms - sporadic, inherited and acquired by infection
GSSF198S and GSSA117V showed similar electrophoretic profiles that were distinguishable from the profile of sCJDMV1 (Fig. 1)
In addition to epitope mapping, a second major distinguishing feature was that, in contrast to sCJDMV1 resistant PrPD (resPrPD), deglycosylation had no significant effect on the electrophoretic mobility of any of the major resPrPD bands observed in GSSF198S and GSSA117V, strongly suggesting that resPrPD
Summary
A well-known feature of human prion diseases is the presence of three distinct etiologic forms - sporadic, inherited and acquired by infection. The sporadic form alone encompasses seven major disease phenotypes [15, 16, 39], and many different variants have been reported for inherited prion diseases [20, 21] This phenotypic variability is believed to be directly related to (and likely encoded in) distinct strains of the disease-related prion protein (PrPD). CJD is characterized by the presence of relatively large resPrPD fragments which, depending on the N-terminus, are classified as type 1 (typically starting at residue G82) and type 2 (starting at residue S97) [15, 26] Both fragment types extend to the C-terminus and include the glycosylphosphatidylinositol (GPI) anchor [16, 39].
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