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Review
. 2013:67:543-64.
doi: 10.1146/annurev-micro-092412-155735. Epub 2013 Jun 28.

Prions and the potential transmissibility of protein misfolding diseases

Allison Kraus  1 , Bradley R Groveman, Byron Caughey
Affiliations
Review

Prions and the potential transmissibility of protein misfolding diseases

Allison Kraus et al. Annu Rev Microbiol. 2013.

Abstract

Prions, or infectious proteins, represent a major frontier in the study of infectious agents. The prions responsible for mammalian transmissible spongiform encephalopathies (TSEs) are due primarily to infectious self-propagation of misfolded prion proteins. TSE prion structures remain ill-defined, other than being highly structured, self-propagating, and often fibrillar protein multimers with the capacity to seed, or template, the conversion of their normal monomeric precursors into a pathogenic form. Purified TSE prions usually take the form of amyloid fibrils, which are self-seeding ultrastructures common to many serious protein misfolding diseases such as Alzheimer's, Parkinson's, Huntington's and Lou Gehrig's (amytrophic lateral sclerosis). Indeed, recent reports have now provided evidence of prion-like propagation of several misfolded proteins from cell to cell, if not from tissue to tissue or individual to individual. These findings raise concerns that various protein misfolding diseases might have spreading, prion-like etiologies that contribute to pathogenesis or prevalence.

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Figures

Figure 1
Figure 1
Potential structural model of PrPRES. An N-terminal extension of a model depicted previously by Cobb, Surewicz, and colleagues (30). PrPSc monomers stack along the protofilament axis, forming stretches of parallel, in-register β-sheets. Each colored strand shows a PrP monomer. Ribbons indicate β-sheets and lines indicate loops and turns. The natural disulfide bond and glycans (yellow structures) are as indicated.
Figure 2
Figure 2
Plausible transmission cycle of chronic wasting disease (CWD). CWD appears to be the most efficient model of natural transmissible spongiform encephalopathy prion spread. ❶ The cycle may begin with uptake of the infectious prion amyloids through routes such as ingestion, inhalation, or contact with the skin or nasal mucosa. ❷ After prion uptake, replication and neuroinvasion occur. ❸ An infected cervid can then shed prions back into the environment through skin, feces, urine, milk, nasal secretions, saliva, placenta, or carcasses, restarting the infectious cycle. (Atomic force micrograph of infectious prion amyloid fibrils reproduced with permission from Reference 123).
Figure 3
Figure 3
Sources of prion infection in humans. Prion diseases in humans can arise spontaneously (black arrows) or following oral or iatrogenic exposure to infectious materials (solid blue arrows). Following oral challenge, infectious prions travel to the gut, where, in animal models at least, they are taken up by the gut mucosa and Peyer’s patches. (Inset) ❶ Incoming infectious prions presumably interact with ❷ native PrPC (yellow square) and ❸ convert the PrPC into PrPSc (green triangles). PrPSc is then transferred to enteric nerves, where it can then spread to the central nervous system. Presumed routes of tissue-to-tissue spread are indicated by dashed red arrows.
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