Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes

Legname, Giuseppe; Nguyen, Hoang-Oanh B.; Peretz, David; Cohen, Fred E.; DeArmond, Stephen J.; Prusiner, Stanley B.

doi:10.1073/pnas.0608970103

Cited by 198 publications

(226 citation statements)

References 53 publications

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“…The strain convergence phenomenon observed during inter-species transmission experiments ( [21,45,174], Sect. 3.3.2) lends support for a relatively finite rather than a continuous portfolio of favored conformations [120]. Recently it has been shown that infectious prions could be spontaneously generated using PMCA from healthy brains unseeded with prions [66].…”

Section: The Conformational Selection Hypothesismentioning

confidence: 92%

Prion agent diversity and species barrier

2008

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-Mammalian prions are the infectious agents responsible for transmissible spongiform encephalopathies (TSE), a group of fatal, neurodegenerative diseases, affecting both domestic animals and humans. The most widely accepted view to date is that these agents lack a nucleic acid genome and consist primarily of PrP Sc , a misfolded, aggregated form of the host-encoded cellular prion protein (PrP C ) that propagates by autocatalytic conversion and accumulates mainly in the brain. The BSE epizooty, allied with the emergence of its human counterpart, variant CJD, has focused much attention on two characteristics that prions share with conventional infectious agents. First, the existence of multiple prion strains that impose, after inoculation in the same host, specific and stable phenotypic traits such as incubation period, molecular pattern of PrP Sc and neuropathology. Prion strains are thought to be enciphered within distinct PrP Sc conformers. Second, a transmission barrier exists that restricts the propagation of prions between different species. Here we discuss the possible situations resulting from the confrontation between species barrier and prion strain diversity, the molecular mechanisms involved and the potential of interspecies transmission of animal prions, including recently discovered forms of TSE in ruminants.prion / strain / misfolding / species barrier / PrP Table of Mammalian prion diseases or transmissible spongiform encephalopathies (TSE) form a group of related, invariably fatal neurodegenerative disorders of both animals and humans. The brain pathology consists of spongiosis, astrocytosis, neuronal loss and neural tissue from affected individuals contains an infectious agent, the prion, setting these diseases apart from other neurodegenerative diseases. Prion replication is thought to involve in essence the self-perpetuating conversion of the host-encoded cellular prion protein (PrP C ) into a misfolded form (PrP Sc ) that tends to aggregate and may be neurotoxic (for reviews [1,157]). Prion replication may also occur in lymphoid tissues but is there poorly if not pathogenic (for review [126], [133]). PrP C is a protein with two variably occupied glycosylation sites. It is attached at the outer of the plasma membrane by a glycosylphosphatidylinositol anchor. Its secondary structure is rich in alpha-helix and the protein is likely to be in a monomeric state in mild detergents. While its precise physiological function has not been assigned, PrP C is essential for prion replication and neurotoxicity to occur [57,129]. Upon infection, PrP C is refolded -without apparent post-translational modification -into beta-sheet -rich PrP Sc , initially in the presence of exogenous PrP Sc and then by an autocatalytic process. It leads to the formation of aggregates, sometimes of amyloid type, that can be differentiated from PrP C because of their partial resistance to protease digestion and of their insolubility into non-denaturing detergents [153]. Proteinase K, the most commonly used protease, di...

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Section: The Conformational Selection Hypothesismentioning

confidence: 92%

Prion agent diversity and species barrier

2008

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“…PrP Sc could occur at very low levels in healthy brains, almost never reaching levels that lead to disease (27). If so, "uninfected" brain homogenates might contain undetected PrP Sc seeds that are concentrated on steel wires (16) and infect PK1 cells in our experiments.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous generation of mammalian prions

Edgeworth

Gros

Alden

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Prions are transmissible agents that cause lethal neurodegeneration in humans and other mammals. Prions bind avidly to metal surfaces such as steel wires and, when surface-bound, can initiate infection of brain or cultured cells with remarkable efficiency. While investigating the properties of metal-bound prions by using the scrapie cell assay to measure infectivity, we observed, at low frequency, positive assay results in control groups in which metal wires had been coated with uninfected mouse brain homogenate. This phenomenon proved to be reproducible in rigorous and exhaustive control experiments designed to exclude prion contamination. The infectivity generated in cell culture could be readily transferred to mice and had strain characteristics distinct from the mouse-adapted prion strains used in the laboratory. The apparent "spontaneous generation" of prions from normal brain tissue could result if the metal surface, possibly with bound cofactors, catalyzed de novo formation of prions from normal cellular prion protein. Alternatively, if prions were naturally present in the brain at levels not detectable by conventional methods, metal surfaces might concentrate them to the extent that they become quantifiable by the scrapie cell assay.cell culture | scrapie | metal | Creutzfeldt-Jakob disease P rions, the transmissible agents that cause fatal neurodegenerative diseases such as Creutzfeldt-Jakob disease in humans, or bovine spongiform encephalopathy and scrapie in animals, occur in the form of various strains and are composed principally or entirely of aggregates of misfolded cellular prion protein (PrP C ), generally referred to as PrP Sc . Replication comes about by autocatalytic conversion of PrP C to the pathogenic isoform (1).In vitro and in vivo studies using model systems have suggested host-encoded cofactors are required to facilitate the propagation of prions (2-5). A variety of polyanionic compounds, lipids, proteoglycans from brain homogenate or purified protein have been shown to stimulate the conversion of PrP C to PrP Sc in vitro (6-10).Steel wire exposed to scrapie prion-infected brain or brain homogenate acquires an extraordinary infectious potential (11,12). Although the amount of protein bound was undetectable by conventional methods, the wires were as effective in eliciting disease as injection of approximately 10 6 LD 50 units in the form of brain homogenate. We have isolated an N2a neuroblastoma-derived cell line, N2aPK1 (i.e., "PK1") (13), that is highly susceptible to infection by a wide spectrum of murine strains, including RML and 22L, but not ME7 and 301C (13,14). When PK1 cells were grown on RML prion-coated wires, adherent cells became PrP Sc -positive, in contrast to neighboring cells, which remained negative, implying that adherence to the prion-coated surface is a prerequisite for infectivity transfer (15). We exploited these observations to detect prions in RML prion-infected brain homogenates diluted as much as 10 −10 , by adsorbing infectivity to steel wire surfaces and sub...

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“…Previous studies have shown that prion strains (including RML, ME7, 22L, 301V, BSE and scrapie) which possessed the least stability in Guanidine Hydrochloride (GdnHCL), exhibited the shortest incubation times in mice [23] , and replicated the most rapidly in the protein misfolding cyclic amplification assay (PMCA) [24] . Our results did not follow this pattern for any of the dendrimer species examined (Table S2).…”

mentioning

confidence: 99%

“…Our results did not follow this pattern for any of the dendrimer species examined (Table S2). For example, 301V proved to be the most resistant prion strain to all dendrimers examined ( Figure 2D and 3) but it was not the most resistant to GdnHCL, [23] nor did it have the longest incubation time in mice (Table S2). This suggests that the features of a prion strain which govern its susceptibility to the different dendrimers examined, differ from those features of a prion strain which define its incubation time and GdnHCl stability.…”

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confidence: 99%