期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：13851-13856
DOI：10.1073/pnas.1610716113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificancePrion diseases are a group of transmissible neurodegenerative disorders. The protein-only hypothesis asserts that transmission of these diseases does not require nucleic acids and that a misfolded, aggregated form of the prion protein represents a self-perpetuating infectious agent. Even though this model is supported by a large body of experimental data, there is a dispute regarding the role of specific cofactors in prion infectivity as well as the structural basis of prion formation. In this work, we show that structurally well-characterized amyloid fibrils generated from bacterially expressed prion protein fragment 23-144 cause prion disease in transgenic and wild-type mice, demonstrating that cofactors are not obligatory for prion formation and providing insight into the structural basis of prion propagation. Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann-Straussler-Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register {beta}-sheet architecture and {beta}-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-Straussler-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 {beta}-sheet core of PrP23-144 fibrils (residues [~]112-139) with a parallel in-register organization of {beta}-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.
