title: Protease-sensitive synthetic prions.
abstract: Prions arise when the cellular prion protein (PrP(C)) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP(Sc). Frequently, PrP(Sc) is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP(Sc) and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600-750 days in Tg4053 mice, which exhibited sPrP(Sc). These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP(Sc).
authors.affiliation: Institute for Neurodegenerative Diseases, University of California, San Francisco, California, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Colby
authors.forename: Rachel
authors.initials: R
authors.lastname: Wain
authors.forename: Ilia V
authors.initials: IV
authors.lastname: Baskakov
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Christina G
authors.initials: CG
authors.lastname: Palmer
authors.forename: Hoang-Oanh B
authors.initials: HO
authors.lastname: Nguyen
authors.forename: Azucena
authors.initials: A
authors.lastname: Lemus
authors.forename: Fred E
authors.initials: FE
authors.lastname: Cohen
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics / Q000378:metabolism* / Q000635:transmission*; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D011994:Recombinant Proteins
chemical_list: D000682:Amyloid; D011328:Prions; D011994:Recombinant Proteins; D010447:Peptide Hydrolases