title: Amyloid fibrils from the N-terminal prion protein fragment are infectious.
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 PrPresfragments 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.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Ignazio
authors.initials: I
authors.lastname: Cali
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Surewicz
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106; witold.surewicz@case.edu.
authors.forename: Witold K
authors.initials: WK
authors.lastname: Surewicz
mesh_terms: D000682:Amyloid / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics; D000818:Animals; D016098:Gerstmann-Straussler-Scheinker Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D017096:Prion Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D000072002:Prion Proteins / Q000009:adverse effects / Q000737:chemistry* / Q000235:genetics; D000072757:Protein Conformation, beta-Strand / Q000235:genetics; D012608:Scrapie / Q000235:genetics / Q000473:pathology; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D000072002:Prion Proteins
keywords: amyloid; infectivity; prion disease; prions