De novo generation of prion strains - PubMed (original) (raw)

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De novo generation of prion strains

David W Colby et al. Nat Rev Microbiol. 2011.

Abstract

Prions are self-replicating proteins that can cause neurodegenerative disorders such as bovine spongiform encephalopathy (also known as mad cow disease). Aberrant conformations of prion proteins accumulate in the central nervous system, causing spongiform changes in the brain and eventually death. Since the inception of the prion hypothesis - which states that misfolded proteins are the infectious agents that cause these diseases - researchers have sought to generate infectious proteins from defined components in the laboratory with varying degrees of success. Here, we discuss several recent studies that have produced an array of novel prion strains in vitro that exhibit increasingly high titres of infectivity. These advances promise unprecedented insight into the structure of prions and the mechanisms by which they originate and propagate.

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Figures

Figure 1

Figure 1

Prions cause neurodegenerative diseases in humans and animals, including (A, from left to right) scrapie in sheep, bovine spongiform encephalopathy in cattle, and chronic wasting disease in deer. (B) The fundamental event in prion disease pathogenesis is the conformational conversion of the prion protein from its normal or cellular form (PrPC) into a disease-causing form (PrPSc). Once formed, PrPSc replicates by inducing the conversion of PrPC into additional PrPSc molecules. (C) Neuropathological features of prion disease include the formation of vacuoles (left) and PrP deposits (right). Brain sections of mice with prion disease were stained with hematoxylin and eosin to visualize vacuoles and anti-PrP antibodies to identify PrP.

Figure 2

Figure 2

Diverse PrP conformations account for the phenotypes displayed by synthetic prion strains. PrP amyloids with high, intermediate, and low stability were formed by altering the length of the recombinant PrP (recPrP) construct and the conditions used for refolding. In mice, the incubation periods and conformational stability of the resulting prion strains were dependent on the conformational stability of the recPrP amyloid from which they originated .

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References

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