Amyloid fibrils from the N-terminal prion protein fragment are infectious
- 14 November 2016
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 113 (48), 13851-13856
- https://doi.org/10.1073/pnas.1610716113
Abstract
Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann–Sträussler–Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register β-sheet architecture and β-sheet core mapping to residues ∼112–139. Here we report that mice (both tga20 and wild type) inoculated with a murine (moPrP23-144) version of these fibrils develop clinical prion disease with a 100% attack rate. Remarkably, even though fibrils in the inoculum lack the entire C-terminal domain of PrP, brains of clinically sick mice accumulate longer proteinase K-resistant (PrPres) fragments of ∼17–32 kDa, similar to those observed in classical scrapie strains. Shorter, Gerstmann–Sträussler–Scheinker-like PrPres fragments are also present. The evidence that moPrP23-144 amyloid fibrils generated in the absence of any cofactors are bona fide prions provides a strong support for the protein-only hypothesis of prion diseases in its pure form, arguing against the notion that nonproteinaceous cofactors are obligatory structural components of all infectious prions. Furthermore, our finding that a relatively short β-sheet core of PrP23-144 fibrils (residues ∼112–139) with a parallel in-register organization of β-strands is capable of seeding the conversion of full-length prion protein to the infectious form has important implications for the ongoing debate regarding structural aspects of prion protein conversion and molecular architecture of mammalian prions.Keywords
Funding Information
- HHS | National Institutes of Health (P01 AI106705)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS083687)
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R01 NS083687)
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