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De novo generation of prion strains

Nature Reviews Microbiology volume 9, pages 771–777 (2011)Cite this article

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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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Figure 1: Prion diseases.
Figure 2: Prion protein conformations and disease incubation periods.

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Acknowledgements

This work was supported by grants from the US National Institutes of Health (AG021601, AG02132, AG010770 and AG031220) as well as by gifts from the G. Harold and Leila Y. Mathers Charitable Foundation, the Sherman Fairchild Foundation and R. Galvin.

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Authors and Affiliations

  1. David W. Colby is at the Department of Chemical Engineering, University of Delaware, Newark, Delaware 19716, USA.,

    David W. Colby

  2. Stanley B. Prusiner is at the Institute for Neurodegenerative Diseases and Department of Neurology, University of California, 513 Parnassus Ave, HSE-774, San Francisco, California 94143, USA.,

    Stanley B. Prusiner

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Correspondence to Stanley B. Prusiner.

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Institute for Neurodegenerative Diseases, University of California, San Francisco

Glossary

Aβ

A short peptide that is cleaved from amyloid precursor protein and forms the amyloid plaques that are found in Alzheimer's disease.

α-synuclein

A protein expressed primarily in neurons and can aggregate to form Lewy bodies (abnormal protein aggregates inside nerve cells), which are found in Parkinson's disease and dementia with Lewy bodies.

Gerstmann–Sträussler–Scheinker syndrome

A genetic neurodegenerative disease in humans that is caused by mutations in the PRNP gene, which encodes the prion protein (PrP).

Huntingtin

A protein that may have a role in microtubule-mediated transport or vesicle function. The expanded polyglutamine repeats within huntingtin cause Huntington's disease.

Microtubule-associated protein tau

A protein that is expressed primarily in neurons and promotes microtubule assembly and stability.

Prion protein

(PrP). A glycosyl phosphatidylinositol-anchored membrane protein that is expressed in many organs and is required for the development of prion diseases. The normal function of PrP is unknown.

Systemic amyloidosis

A disease in which amyloid is deposited in various organs outside the central nervous system.

Synthetic prions

Infectious proteins that can be created from minimal components in the laboratory and demonstrate infectivity in living organisms.

Tauopathies

Neurodegenerative diseases that are caused by the misprocessing and aggregation of microtubule-associated protein tau, which results in neurofibrillary tangles, paired helical filaments and/or Pick bodies (silver-staining, spherical protein aggregations) in the brain.

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Colby, D., Prusiner, S. De novo generation of prion strains. Nat Rev Microbiol 9, 771–777 (2011). https://doi.org/10.1038/nrmicro2650

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