Chapter Nine - Transmission and Replication of Prions

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Abstract

Transmissible spongiform encephalopathies (TSEs) are a group of progressive, invariably fatal diseases that affect the nervous system of many mammals including humans.

The key molecular event in the pathogenesis of TSEs is the conversion of the cellular prion protein PrPC into a disease-associated isoform PrPSc. The “protein-only hypothesis” argues that PrPSc itself is the infectious agent. In effect, PrPSc can adopt several structures that represent different prion strains.

The interspecies transmission of TSEs is difficult because of differences between the host and donor primary PrP sequence. However, transmission is not impossible as this occurred when bovine spongiform encephalopathy spread to humans causing variant Creutzfeldt–Jakob disease (vCJD).

This event determined a need for a thorough understanding of prion replication and transmission so that we could be one step ahead of further threats for human health. This chapter focuses on these concepts and on new insights gained into prion propagation mechanisms.

Section snippets

The “Protein-Only” Hypothesis

The longest known transmissible spongiform encephalopathy (TSE), scrapie, was first thought to be a muscle disease caused by parasites1 or by “filterable” virus of slow progression.2 Soon, however, there was more and more evidence to suggest that the scrapie agent was something different from a virus. It was noted to be resistant to treatments that destroy nucleic acids2, 3 but susceptible to treatments that disrupt protein structure.4, 5, 6, 7, 8 In parallel, attempts to identify a

Prion Transmissibility and the Species Barrier

One of the main characteristics that differentiates TSEs from other neurodegenerative diseases caused by protein misfolding and aggregation is their transmissibility among individuals of the same species and other species. Transmission between different species is an especially worrying characteristic since a given prion disease could “jump” from its natural host to other species including humans.

Fortunately, because of the so-called species barrier, interspecies transmission is not so

Concluding Remarks

Advances in the study of prion transmission and replication have paralleled the development of appropriate tools and technologies shedding some light on the still obscure pieces of the complicated puzzle of TSEs.

The molecular mechanisms of prion replication have not been clearly defined. Neither is it known how strain information is maintained and transmitted or which mechanisms define the tropisms of prion strains. Resolving these issues may also significantly impact other protein misfolding

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