Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da

Bellinger-Kawahara, Carolyn; Kempner, Ellis S.; Groth, Darlene; Gabizon, Ruth; Prusiner, Stanley B.

doi:10.1016/0042-6822(88)90569-7

Cited by 135 publications

(74 citation statements)

References 34 publications

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“…of monomers ϭ reaction volume 100 l ϫ limiting dilution 10 Ϫ11 ϫ estimated PrP Sc concentration 400 ng/ml ϫ monomeric PrP molecular weight 35,000 Ϭ Avogadro's number). Interestingly, this calculated value is close to the measured minimum size of brain-derived infectious scrapie particles (2-6 PrP Sc monomers) (27)(28)(29) as well as the minimum number of PrP Sc monomers (equal to 26) required to initiate serial PMCA propagation reactions in crude homogenates (26). It should be noted that approximately half of the PrP C preparations generated were less sensitive, i.e., required seed more concentrated than a 10 Ϫ11 dilution of PMCA product to initiate a three-round PMCA propagation experiment; such preparations were not used for subsequent experiments.…”

Section: Resultsmentioning

confidence: 85%

Formation of native prions from minimal components in vitro

Deleault¹,

Harris²,

Rees³

et al. 2007

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

585

635

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The conformational change of a host protein, PrP C , into a disease-associated isoform, PrP Sc , appears to play a critical role in the pathogenesis of prion diseases such as Creutzfeldt–Jakob disease and scrapie. However, the fundamental mechanism by which infectious prions are produced in neurons remains unknown. To investigate the mechanism of prion formation biochemically, we conducted a series of experiments using the protein misfolding cyclic amplification (PMCA) technique with a preparation containing only native PrP C and copurified lipid molecules. These experiments showed that successful PMCA propagation of PrP Sc molecules in a purified system requires accessory polyanion molecules. In addition, we found that PrP Sc molecules could be formed de novo from these defined components in the absence of preexisting prions. Inoculation of samples containing either prion-seeded or spontaneously generated PrP Sc molecules into hamsters caused scrapie, which was transmissible on second passage. These results show that prions able to infect wild-type hamsters can be formed from a minimal set of components including native PrP C molecules, copurified lipid molecules, and a synthetic polyanion.

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Section: Resultsmentioning

confidence: 85%

Formation of native prions from minimal components in vitro

Deleault¹,

Harris²,

Rees³

et al. 2007

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

585

635

View full text Add to dashboard Cite

show abstract

“…60,61 Rather, such modeling studies suggest that small oligomers would function as the most infectious units. 62,63 Consistent with these predictions, ionizing radiation, [64][65][66] fractionation, 67,68 and denaturation 69 studies support a minimum infectious complex of ∼5 PrP subunits, with peak infectivity in the range of 14-28 monomers. 68 Moreover, the threshold behavior of scrapie appearance, in which the sporadic rate of disease is exceedingly low, can only be explained by a mechanism in which multiple, spontaneously arising PrP Sc monomers must come together to form a stable complex that functions as an active template.…”

Section: Regeneration Of the Prion Template In Vivosupporting

confidence: 62%

Prion Propagation: The Role of Protein Dynamics

Pezza

Serio

2007

Prion

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“…But both UV and ionizing radiation inactivation studies as well as physical studies have eliminated the possibility of a large nucleic acid hiding within purified preparations of prions (110)(111)(112). Only oligonucleotides of fewer than 50 bases were found at a concentration of one molecule per ID 50 unit in prion preparations highly enriched for scrapie infectivity (113,114).…”

mentioning

confidence: 99%

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

Chisholm

Dahlbeck

Krishnamurthy

et al. 2005

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

137

138

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Prions are unprecedented infectious pathogens that cause a group of invariably fatal neurodegenerative diseases by an entirely novel mechanism. Prion diseases may present as genetic, infectious, or sporadic disorders, all of which involve modification of the prion protein (PrP). Bovine spongiform encephalopathy (BSE), scrapie of sheep, and Creutzfeldt-Jakob disease (CJD) of humans are among the most notable prion diseases. Prions are transmissible particles that are devoid of nucleic acid and seem to be composed exclusively of a modified protein (PrP Sc ). The normal, cellular PrP (PrP C ) is converted into PrP Sc through a posttranslational process during which it acquires a high ␤-sheet content. The species of a particular prion is encoded by the sequence of the chromosomal PrP gene of the mammals in which it last replicated. In contrast to pathogens carrying a nucleic acid genome, prions appear to encipher strain-specific properties in the tertiary structure of PrP Sc . Transgenetic studies argue that PrP Sc acts as a template upon which PrP C is refolded into a nascent PrP Sc molecule through a process facilitated by another protein. Miniprions generated in transgenic mice expressing PrP, in which nearly half of the residues were deleted, exhibit unique biological properties and should facilitate structural studies of PrP Sc . While knowledge about prions has profound implications for studies of the structural plasticity of proteins, investigations of prion diseases suggest that new strategies for the prevention and treatment of these disorders may also find application in the more common degenerative diseases.

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Scrapie prion liposomes and rods exhibit target sizes of 55,000 Da

Cited by 135 publications

References 34 publications

Formation of native prions from minimal components in vitro

Formation of native prions from minimal components in vitro

Prion Propagation: The Role of Protein Dynamics

Molecular characterization of proteolytic cleavage sites of the Pseudomonas syringae effector AvrRpt2

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