Biochemical and conformational variability of human prion strains in sporadic Creutzfeldt-Jakob disease

The pathogenesis of prion (PrP) diseases is thought to be related to confor mational changes of a normal cellular protei n, PrPC, into a protease resis tant protei n ca I led PrPSc, wh ich is infectious by itself. A difficulty with this 'protein only' hypothesis is the existence of numerous PrP strain s, that require PrPSc to have multiple conformations. Sporadic Creutzfeldt- Jakob disease (CJD), which accounts for nearly 80% of human prionoses, was reported to include at least two 'strains' termed types 1 and 2 which diffe r by electrophoretic patterns of their proteinase K (PK)-resistant fragment s (PrP27-30). We have analyzed the biochemical and structural properties of PrPSc and PrP27-30 isolates from six sporadic CJD patients. Fourier transf orm-infra-red spectroscopy, PrP27-30 glycosylation patterns and studies of PK sensitivity revealed a striking heterogeneity. Furthermore, one isolate yielded a PrP27-30 fragment with a lower mobility clearly different from pr eviously described sporadic CJD types. Although the average beta-sheet cont ent was higher among type 1 isolates, there was overlap between the two typ es, Our study suggests that hu man sporadic CJD-related prions display a si gnificant heterogeneity. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.