Formation of native prions from minimal components
            <i>in vitro</i>

Deleault, Nathan R.; Harris, Brent T.; Rees, Judy R.; Supattapone, Surachai

doi:10.1073/pnas.0702662104

“…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]. It would be of interest to see to which extent the spectrum of artificially created PrP Sc conformations will overlap that of the natural one.…”

Section: The Conformational Selection Hypothesismentioning

confidence: 99%

Prion agent diversity and species barrier

Béringue

¹

,

Vilotte

²

,

Laude

³

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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“…Thus, 269 it has been suggested that an as yet unidentified polyanion may be a component of 270 the infectious prion particle (13). The search for a more complete understanding of 271 the causative agent(s) of PrP--C to PrP--Sc conversion has continued (13). 272 273…”

Section: Transmissible Spongiform Encephalopathymentioning

confidence: 99%

“…Teflon 267 beads increase the amplification rate in prion PMCA reactions (PCMAb) for 268 unknown reasons, as does addition of the amphipathic glycoside saponin (15). Thus, 269 it has been suggested that an as yet unidentified polyanion may be a component of 270 the infectious prion particle (13). The search for a more complete understanding of 271 the causative agent(s) of PrP--C to PrP--Sc conversion has continued (13).…”

Section: Transmissible Spongiform Encephalopathymentioning

confidence: 99%

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Reddy

¹

2017

Preprint

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A scientific theory or hypothesis is presented, in which mineral particles may play a pivotal role in the prion disease transmissible spongiform encephalopathy (TSE), and possibly also in other protein--misfolding diseases. Montmorillonite clay (Mte) and other minerals are known to bind to scrapie prion protein (PrP--Sc) in soil. The hypothesis is explored that, in transmissible spongiform encephalopathy, Mte or other mineral particles, upon contact with lipids, such as in the gut or at the cell plasma membrane, may interact with lipids or with lipid rafts. The minerals may catalyze formation of lipid vesicles, and might also be capable of inducing lipid raft clustering or other lipid raft or plasma membrane changes. Some of these lipid vesicles or rafts might then contain or bind PrP--Sc, and sometimes also contain montmorillonite or the mineral catalyst. Mte--PrP--Sc or the affected lipid vesicles/particles could also promote PrP--C to PrP--Sc conversion by providing conditions for misfolding. These conditions provided for protein misfolding may include the following: multiple unique compartments providing sizes, shapes or aqueous/lipid environments that promote varied folding conformations, presence of an anion (Mte), negative--charge (Mte), lipid membrane mimetic (e.g. associated lipid particle, vesicle or raft), interaction with bound or contained PrP--Sc, presence of bound copper, and/or copper binding affinity. Mte--catalyzed lipid vesicles are proto--cell--like entities, making them potential candidates to be part of the infectious particle in prion disease, which can behave like an infectious organism but does not appear to depend on nucleic acid. Lipid vesicles or rafts may resemble endosomes, which would be consistent with reports of prion being transported and formed along an endosome--like pathway. Additionally, the vesicles or rafts could accumulate intra--cellularly, and might form tubulovesicular structures, which are hallmarks of prion disease. Potential applications of this theory to more common protein misfolding diseases, Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, are discussed. This theory, which I term the mineral--lipid prion hypothesis, provides a basis for potential novel interventions in the field of prion and protein--misfolding diseases. In addition, this theory suggests that similar silicate--or mineral--catalyzed lipid vesicles/liposomes might be further explored as useful compartments that could be manipulated in order to deliver molecules or even proteins to or from cells.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2982v1 | CC BY 4.0

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“…This hypothesis suggests that abnormally--261 folded PrP--Sc protein itself is the transmissible and infectious agent causing TSE 262 disease. However, exposure to PrP--Sc alone results in only limited conversion of 263 normal PrP--C. Further and of equal interest, it has been demonstrated that PrP--Sc 264 can actually be formed without provision of pre--existing PrP--Sc, using a protein 265 misfolding cyclic amplification (PMCA) technique relying on PrP--C, lipid molecules, 266 and a synthetic polyanion such as use of poly(A) RNA substrate (13,15). Teflon 267 beads increase the amplification rate in prion PMCA reactions (PCMAb) for 268 unknown reasons, as does addition of the amphipathic glycoside saponin (15).…”

Section: Transmissible Spongiform Encephalopathymentioning

confidence: 99%

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Reddy

¹

2017

Preprint

0

View full text Add to dashboard Cite

A scientific theory or hypothesis is presented, in which mineral particles may play a pivotal role in the prion disease transmissible spongiform encephalopathy (TSE), and possibly also in other protein--misfolding diseases. Montmorillonite clay (Mte) and other minerals are known to bind to scrapie prion protein (PrP--Sc) in soil. The hypothesis is explored that, in transmissible spongiform encephalopathy, Mte or other mineral particles, upon contact with lipids, such as in the gut or at the cell plasma membrane, may interact with lipids or with lipid rafts. The minerals may catalyze formation of lipid vesicles, and might also be capable of inducing lipid raft clustering or other lipid raft or plasma membrane changes. Some of these lipid vesicles or rafts might then contain or bind PrP--Sc, and sometimes also contain montmorillonite or the mineral catalyst. Mte--PrP--Sc or the affected lipid vesicles/particles could also promote PrP--C to PrP--Sc conversion by providing conditions for misfolding. These conditions provided for protein misfolding may include the following: multiple unique compartments providing sizes, shapes or aqueous/lipid environments that promote varied folding conformations, presence of an anion (Mte), negative--charge (Mte), lipid membrane mimetic (e.g. associated lipid particle, vesicle or raft), interaction with bound or contained PrP--Sc, presence of bound copper, and/or copper binding affinity. Mte--catalyzed lipid vesicles are proto--cell--like entities, making them potential candidates to be part of the infectious particle in prion disease, which can behave like an infectious organism but does not appear to depend on nucleic acid. Lipid vesicles or rafts may resemble endosomes, which would be consistent with reports of prion being transported and formed along an endosome--like pathway. Additionally, the vesicles or rafts could accumulate intra--cellularly, and might form tubulovesicular structures, which are hallmarks of prion disease. Potential applications of this theory to more common protein misfolding diseases, Alzheimer's disease, Parkinson's disease, and Amyotrophic lateral sclerosis, are discussed. This theory, which I term the mineral--lipid prion hypothesis, provides a basis for potential novel interventions in the field of prion and protein--misfolding diseases. In addition, this theory suggests that similar silicate--or mineral--catalyzed lipid vesicles/liposomes might be further explored as useful compartments that could be manipulated in order to deliver molecules or even proteins to or from cells.PeerJ Preprints | https://doi.org/10.7287/peerj.preprints.2982v1 | CC BY 4.0

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Formation of native prions from minimal components in vitro

Cited by 578 publications

References 55 publications

Prion agent diversity and species barrier

Prion agent diversity and species barrier

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

Beyond the protein-only hypothesis: A novel mineral-lipid hypothesis in prion and protein-misfolding disease

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