Generating a Prion with Bacterially Expressed Recombinant Prion Protein
By Fei Wang, Xinhe Wang, C. Yuan, Jiyan Ma. Science, 2010
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Recombinant Infectious Prions Prion diseases are a group of fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy in cows. The prion hypothesis states that the infectious agent of these diseases is an aberrant conformational isoform of the normal prion protein (PrPC), a glycosylphosphatidylinositol-anchored cell surface protein enriched in the central nervous system. The final proof for the prion hypothesis is to convert bacterially expressed recombinant PrP into an infectious prion, but this has been difficult to achieve. F. Wang et al. (p. 1132, published online 28 January; see the Perspective by Supattapone) put recombinant PrP purified from bacteria into mice and obtained all the characteristics of the infectious agent in prion disease. The recombinant form is not only resistant to proteinase-K, but also shows infectivity in cultured cells and causes rapid disease progression in wild-type mice, yielding both the behavioral and the neuropathological symptoms. Recombinant prion protein recapitulates the characteristics of the infectious agent in prion disease. The prion hypothesis posits that a misfolded form of prion protein (PrP) is responsible for the infectivity of prion disease. Using recombinant murine PrP purified from Escherichia coli, we created a recombinant prion with the attributes of the pathogenic PrP isoform: aggregated, protease-resistant, and self-perpetuating. After intracerebral injection of the recombinant prion, wild-type mice developed neurological signs in ~130 days and reached the terminal stage of disease in ~150 days. Characterization of diseased mice revealed classic neuropathology of prion disease, the presence of protease-resistant PrP, and the capability of serially transmitting the disease; these findings confirmed that the mice succumbed to prion disease. Thus, as postulated by the prion hypothesis, the infectivity in mammalian prion disease results from an altered conformation of PrP.
Subfields: Molecular Biology, Neurology, Nutrition and Dietetics
View Paper: https://www.semanticscholar.org/paper/5de12fc910cdb23be08a5224e63d2eb7605dae15
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Citations in the corpus
- The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease (2012, background): “Indeed , it is now possible to induce prion disease in wild-type mice by simply inoculating recombinant prion protein (PrP) that has been previously folded into a self-templating form in the presence of poly-anions and lipid in vitro (Wang et al., 2010, 2011a, 2011b).”
- Pathogenic Protein Seeding in Alzheimer’s Disease and Other Neurodegenerative Disorders (2011, background): “It is possible that the aggregation of synthetic Ab under suitable (but as yet undefined) conditions will yield a more effective in vivo seed, as was recently demonstrated for PrP.(58) The differential seeding ability of synthetic versus natural Ab aggregates (which may contain additional factors) s”