Abstract
The mammalian prions replicate by converting cellular prion protein (PrPC) into pathogenic conformational isoform (PrPSc). Variations in prions, which cause different disease phenotypes, are referred to as strains. The mechanism of high-fidelity replication of prion strains in the absence of nucleic acid remains unsolved. We investigated the impact of different conformational characteristics of PrPSc on conversion of PrPC in vitro using PrPSc seeds from the most frequent human prion disease worldwide, the Creutzfeldt-Jakob disease (sCJD). The conversion potency of a broad spectrum of distinct sCJD prions was governed by the level, conformation, and stability of small oligomers of the protease-sensitive (s) PrPSc. The smallest most potent prions present in sCJD brains were composed only of∼20 monomers of PrPSc. The tight correlation between conversion potency of small oligomers of human sPrPSc observed in vitro and duration of the disease suggests that sPrPSc conformers are an important determinant of prion strain characteristics that control the progression rate of the disease.
Highlights
The yeast, fungal, and mammalian prions determine heritable and infectious traits, and behave like proteinaceous genes [1]
Mammalian prion diseases were originally characterized by accumulation of protease-resistant prion protein (PrPSc), often forming large amyloid deposits and fibrils
The apparent absence of protease-resistant PrPSc or amyloid fibrils in growing number of prion diseases raised several fundamental questions; whether presumably protease-sensitive forms of PrPSc exist as distinct conformers; and whether they comprise the initial steps in prion replication or are related to the alternative misfolding pathway generating noninfectious aggregates
Summary
The yeast, fungal, and mammalian prions determine heritable and infectious traits, and behave like proteinaceous genes [1]. The number of prion strains that cause sCJD is not known [4,5,6] and, in contrast to growing structural characterization of rodent prions [7,8,9], no direct structural data are available for pathogenic prion protein (PrPSc) present in sCJD brains beyond the evidence that it is variably resistant to proteolytic digestion [5,10,11]. Mammalian prion diseases were originally characterized by deposits of protease-resistant prion protein (PrPSc), often forming large amyloid plaques and fibrils [12,13]. The variable specific infectivity of rPrPSc and apparent absence of protease-resistant PrPSc or amyloid fibrils in growing number of prion diseases [11,19] lead some researchers to question the causative link between rPrPSc and prion infectivity [6,20,21]
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