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Rapid formation of amyloid from -monomeric recombinant human PrP in vitro

Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom

(RECEIVED July 20, 2004; FINAL REVISION October 20, 2004; ACCEPTED December 3, 2004)

The infectious agent of prion diseases is identified with PrP^Sc, a -rich, amyloidogenic and partially protease resistant isoform of the cellular glycoprotein, PrP^C. To understand the process of prion formation in vivo, we and others have studied defined misfolding pathways of recombinant PrP in vitro. The low-level infectivity of the in vitro misfolded murine PrP amyloid has recently been reported. Here we analyze the in vitro kinetics of amyloid formation from recombinant human PrP^90–231 in vitro in the context of two common allelic forms of PrP found in human populations that are associated with differences in prion disease susceptibility and pathological phenotype. We show that human PrP amyloid forms readily from its PrP^C-like state in vitro, that the lag time of the reaction can be further shortened by the presence of a "seed" of pre-formed PrP amyloid, and that amyloid propagation is more complex than a simple crystallization process. We further show that the kinetics of amyloid formation do not differ between the Met129 and Val129 allelomorphs of human PrP, and that amyloid from each functions as an equally effective seed in heterologous, as in homologous amyloid reactions. The results could illuminate the process of amyloid formation in vivo as well as help understanding prion pathogenesis.

Keywords: amyloid; prion; human PrP; polymorphism 129; CJD; misfolding

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041000905.

Reprint requests to: William James, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; e-mail: william.james{at}path.ox.ac.uk; fax: (+44) 1865 285756.

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