The controversial protein-only hypothesis of prion propagation

  title={The controversial protein-only hypothesis of prion propagation},
  author={Claudio Soto and Joaqu{\'i}n Castilla},
  journal={Nature Medicine},
  volume={10 Suppl 2},
Prion diseases are some of the most intriguing infectious disorders affecting the brains of humans and animals. The prevalent hypothesis proposes that the infectious agent is a misfolded protein that propagates in the absence of nucleic acid by transmission of its altered folding to the normal host version of the protein. This article details the evidence for and against the prion hypothesis, including results of recent studies in yeast, in which a prion phenomenon has also been identified. The… 
Generation of prions in vitro and the protein-only hypothesis
Recent reports on the in vitro generation of prions have settled all doubts that the misfolded prion protein (PrPSc) is the key component in propagating infectivity, but the authors still do not understand completely the mechanism of prion replication and whether or not other cellular factors besides PrPSc are required for infectivity.
The intriguing prion disorders
  • K. Abid, C. Soto
  • Biology, Medicine
    Cellular and Molecular Life Sciences CMLS
  • 2006
Recent developments concerning the protein-only hypothesis as well as the possible involvement of cellular factors in PrPC to PrPSc conformational change and their influence on the pathogenesis of prion diseases are reviewed.
Prion hypothesis: the end of the controversy?
  • C. Soto
  • Biology
    Trends in biochemical sciences
  • 2011
Mammalian prions
The recent isolation of various subsets of abnormal PrP, along with the improved biochemical tools and infectivity detection assays have shed light on the diversity of abnormalPrP protein and may give insights into the features of the more infectious subset of normal PrP.
The prion strain phenomenon: molecular basis and unprecedented features.
In Vitro Generation of Infectious Scrapie Prions
High-resolution structure of infectious prion protein: the final frontier
The importance of, challenges for and recent progress toward elucidating the elusive structure of PrPSc are highlighted, arguably the major pending milestone to reach in understanding prions.
Biology and Genetics of PrP Prion Strains.
An overview of the prion-strain phenomenon is provided and the role of strain adaptation in drug resistance is described and the presence of distinct conformational strains in other neurodegenerative disorders is described.
Diagnosing prion diseases: needs, challenges and hopes
  • C. Soto
  • Medicine
    Nature Reviews Microbiology
  • 2004
Prion diseases are among the most intriguing infectious diseases and are associated with unconventional proteinaceous infectious agents known as prions. Prions seem to lack nucleic acid and propagate
Cell‐free propagation of prion strains
It is shown that PrPSc generated in vitro by protein misfolding cyclic amplification from five different mouse prion strains maintains the strain‐specific properties, suggesting that strain variation is dependent onPrPSc properties and providing additional support for the prion hypothesis.


Prion diseases of humans and animals: their causes and molecular basis.
The appearance of a novel human prion disease, variant CJD, and the clear experimental evidence that it is caused by exposure to BSE has highlighted the need to understand the molecular basis of prion propagation, pathogenesis, andThe barriers limiting intermammalian transmission.
Species-barrier-independent prion replication in apparently resistant species.
The existence of subclinical forms of prion infection with important public health implications are demonstrated, both with respect to iatrogenic transmission from apparently healthy humans and dietary exposure to cattle and other species exposed to bovine spongiform encephalopathy prions.
Transmission of the BSE Agent to Mice in the Absence of Detectable Abnormal Prion Protein
Although all of the mice injected with homogenate from BSE-infected cattle brain exhibited neurological symptoms and neuronal death, more than 55 percent had no detectable PrPres, suggesting that a further unidentified agent may actually transmit BSE.
Cell-free formation of protease-resistant prion protein
The conversion of PrPc to protease-resistant forms similar to PrPSc in a cell-free system composed of substantially purified constituents is reported, providing direct evidence that PrP sc derives from specific PrP c–PrPSc interactions.
Protein-only transmission of three yeast prion strains
The protein-only nature of prion strains in a yeast model is demonstrated, the [PSI] genetic element that enhances the read-through of nonsense mutations in the yeast Saccharomyces cerevisiae is demonstrated and strain-specific infectivity is demonstrated.
RNA molecules stimulate prion protein conversion
It is reported that stoichiometric transformation of PrPC to PrPres in vitro requires specific RNA molecules, suggesting that host-encoded stimulatory RNA molecules may have a role in the pathogenesis of prion disease.
Conformational variations in an infectious protein determine prion strain differences
A high-efficiency protocol for infecting yeast with the [PSI+] prion using amyloids composed of a recombinant Sup35 fragment (Sup-NM) is reported, and it is established that Sup-NM adopts an infectious conformation before entering the cell, fulfilling a key prediction of the prion hypothesis.
BSE and Prions: Uncertainties About the Agent
In his Perspective, Cheseboro outlines the evidence that prions are composed only of protein (an idea advanced by recent Nobel Prize winner Stanley Prusiner) and the evidence against that hypothesis.
Non-genetic propagation of strain-specific properties of scrapie prion protein
Self-propagation of PrPSc polymers with distinct three-dimensional structures could be the molecular basis of scrapie strains, providing evidence that the protein-only model of infectious agents causing scrapie and other transmissible spon-giform encephalopathies is feasible.
Evidence for the prion hypothesis: induction of the yeast [PSI+] factor by in vitro- converted Sup35 protein.
Starting with purified, bacterially produced protein, a [PSI(+)]-inducing agent based on an altered (prion) conformation of the yeast Sup35 protein is created and introduced into the cytoplasm of living yeast using a liposome transformation protocol.