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For Prion Mutations, It's Location, Location, Location

Transmissible spongiform encephalopathies, or prion diseases, are a group of mammalian neurodegenerative disorders marked by the misfolding and aggregation of the prion protein (PrP). The self-perpetuating conversion of the monomeric, soluble PrP to a polymeric, amyloid-forming conformer is believed to be the critical molecular event in the pathogenesis of these diseases. Although the biology of prion diseases remains enigmatic, recent findings suggest that mutations associated with familial human prion diseases may promote conversion of the prion protein by influencing its folding pathway and/or energy landscape.

PrP23-144 amyloid fibrils.

In this Paper of the Week, Eric M. Jones and colleagues explore the effects of three pathogenic PrP mutations and an M129V polymorphism, all occurring in the unstructured N-terminal region of PrP. In their experiments, they use the human PrP fragment 23-144, which is able to undergo autocatalytic conformational conversion. Jones et al. found that none of the amino acid substitutions altered amyloidogenic propensity or affected the ability of individual mutant PrP23-144 amyloid fibrils to induce (seed) conformation conversion of monomeric wild-type protein. However, the M129V polymorphism did strongly influence the conformation of the amyloid fibrils. Intriguingly, the structural features distinguishing Met-129 and Val-129 were not transmissible by cross-seeding. From their findings, the authors hypothesize that biological behaviors can be localized to subregions of the prion protein and suggest which regions are responsible for particular behaviors.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 8190-8196

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