The molecular biology of prion propagation

Anthony R. Clarke, Graham S. Jackson, John Collinge

Abstract

Prion diseases such as Creutzfeldt–Jakob disease (CJD) in humans and scrapie and bovine spongiform encephalopathy (BSE) in animals are associated with the accumulation in affected brains of a conformational isomer (PrPSc) of host–derived prion protein (PrPC). According to the protein–only hypothesis, PrPSc is the principal or sole component of transmissible prions. The conformational change known to be central to prion propagation, from a predominantly α–helical fold to one predominantly comprising β structure, can now be reproduced in vitro, and the ability of β–PrP to form fibrillar aggregates provides a plausible molecular mechanism for prion propagation. The existence of multiple prion strains has been difficult to explain in terms of a protein–only infectious agent but recent studies of human prion diseases suggest that strain–specific phenotypes can be encoded by different PrP conformations and glycosylation patterns. The experimental confirmation that a novel form of human prion disease, variant CJD, is caused by the same prion strain as cattle BSE, has highlighted the pressing need to understand the molecular basis of prion propagation and the transmission barriers that limit their passage between mammalian species. These and other advances in the fundamental biology of prion propagation are leading to strategies for the development of rational therapeutics.

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