Amyloid fibrils from the N-terminal prion protein fragment are infectious

Proc Natl Acad Sci U S A. 2016 Nov 29;113(48):13851-13856. doi: 10.1073/pnas.1610716113. Epub 2016 Nov 14.


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: amyloid; infectivity; prion disease; prions.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / adverse effects
  • Amyloid / chemistry*
  • Amyloid / genetics
  • Animals
  • Gerstmann-Straussler-Scheinker Disease / etiology
  • Gerstmann-Straussler-Scheinker Disease / genetics*
  • Gerstmann-Straussler-Scheinker Disease / pathology
  • Humans
  • Mice
  • Prion Diseases / etiology
  • Prion Diseases / genetics*
  • Prion Diseases / pathology
  • Prion Proteins / adverse effects
  • Prion Proteins / chemistry*
  • Prion Proteins / genetics
  • Protein Conformation, beta-Strand / genetics
  • Scrapie / genetics
  • Scrapie / pathology
  • Spectroscopy, Fourier Transform Infrared


  • Amyloid
  • Prion Proteins