Scrapie prions aggregate to form amyloid-like birefringent rods

Prusiner, Stanley B.; McKinley, Michael P.; Bowman, Karl M.; Bolton, David; Bendheim, Paul E.; Groth, Darlene; Glenner, George G.

doi:10.1016/0092-8674(83)90168-x

Cited by 1,007 publications

(739 citation statements)

References 48 publications

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“…Because of its glycine-and proline-rich amino acid sequence, neither c~-helix nor [3-sheet structure has been predicted in this region [8]. The protein found in the PrP sc amyloid, sometimes designated PrP 27-30, lacks the N-terminal region due to proteolytic truncation and it is considered that the N-terminal region is not directly related to the amyloid formation [13]. However, the octapeptide repeat is highly conserved among mammalian PrP c' proteins [14], implying some functional and structural roles of the octapeptide.…”

Section: Introductionmentioning

confidence: 99%

Metal‐dependent α‐helix formation promoted by the glycine‐rich octapeptide region of prion protein

1996

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Prion diseases share a common feature in that the normal cellular prion .protein (PrP c) converts to a proteaseresistant isoform PrP ~c. The c¢-helix-rich C-terminal half of PrP c is partly converted into []-sheet in PrP so. We have examined by Raman spectroscopy the structure of an octapeptide PHGGGWGQ that appears in the N-terminal region of PrP c and a longer peptide containing the octapeptide region. The peptides do not assume any regular structure without divalent metal ions, whereas Cu(II) binding to the HGGG segment induces formation of co-helical structure on the C-terminal side of the peptide chain. The N-terminal octapeptide of prion protein may be a novel structural motif that acts as a promoter of c~-helix formation.

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Section: Introductionmentioning

confidence: 99%

Metal‐dependent α‐helix formation promoted by the glycine‐rich octapeptide region of prion protein

1996

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“…Prions are present in the blood of infected animals, since the disease has been shown to be transmitted by transfusionÅ [12].Å HoweverÅ becauseÅ ofÅ theÅ highÅ specificÅ infectivity of purified prion preparations (as high as 10 11 infectious units (IU) per milligram of protein purified fromÅ SyrianÅ hamstersÅ inoculatedÅ withÅ strainÅ 263K)Å [13], and the fact that in rodent models of TSE, blood contains 5 to 10 IU/mL in preclinical animals and a maximum of about 100 IU/mL at the time of disease onset, it has been estimated that blood contains about 0.05Å toÅ 1.0Å pgÅ (30Å -Å 625Å amol)Å ofÅ PrP ScÅ perÅ mLÅ [14].…”

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confidence: 99%

Mass spectrometric detection of attomole amounts of the prion protein by nanoLC/MS/MS

Onisko¹,

Dynin²,

Requena

et al. 2007

J. Am. Soc. Mass Spectrom.

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Sensitive quantitation of prions in biological samples is an extremely important and challenging analytical problem. Prions are the cause of several fatal neurodegenerative diseases known as transmissible spongiform encephalopathies (TSEs). At this time, there are no methods to diagnose TSEs in live animals or to assure a prion-free blood supply for humans. Prions have been shown to be present in blood by transfusion experiments, but based on the amount of infectivity found in these types of experiments, the amount of misfolded prion protein in blood is estimated to be only 30 to 625 amol/mL. More sensitive detection of prions in brain would allow earlier detection of disease and assure a safer food supply. We studied quantitation of the prion protein by use of nanoscale liquid chromatography coupled to a tandem mass spectrometer using the multiple reaction monitoring mode of operation. We developed a method based on the detection of VVEQMCTTQYQK obtained by reduction, alkylation, and digestion with trypsin of the prion protein.

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“…Fourier transform infrared spectroscopy and circular dichroism (CD) demonstrate that PrP C is predominantly ␣-helical (42%) with little ␤-sheet structure (3%). However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al, 1983;Pan et al, 1993;Safar et al, 1993;Baldwin et al, 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al, 1993;Safar et al, 1993;Baldwin et al, 1994).…”

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confidence: 99%

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

Rymer

Good

2000

Journal of Neurochemistry

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Prion diseases are neurodegenerative disorders associated with a conformational change in the normal cellular isoform of the prion protein, PrP C , to an abnormal scrapie isoform, PrP SC . Unlike the ␣-helical PrP C , the protease-resistant core of PrP SC is predominantly ␤-sheet and possesses a tendency to polymerize into amyloid fibrils. We performed experiments with two synthetic human prion peptides, and , to determine how peptide structure affects neurotoxicity and protein-membrane interactions. Peptide solutions possessing ␤-sheet and amyloid structures were neurotoxic to PC12 cells in vitro and bound with measurable affinities to cholesterol-rich phospholipid membranes at ambient conditions, but peptide solutions lacking stable ␤-sheet structures and amyloid content were nontoxic and possessed less than one tenth of the binding affinities of the amyloid-containing peptides. Regardless of structure, the peptide binding affinities to cholesterol-depleted membranes were greatly reduced. These results suggest that the ␤-sheet and amyloid structures of the prion peptides give rise to their toxicity and membrane binding affinities and that membrane binding affinity, especially in cholesterol-rich environments, may be related to toxicity. Our results may have significance in understanding the role of the fibrillogenic cerebral deposits associated with some of the prion diseases in neurodegeneration and may have implications for other amyloidoses. Key Words: Circular dichroismSpongiform encephalopathies-Cell membranes. J. Neurochem. 75, 2536Neurochem. 75, -2545Neurochem. 75, (2000.The prion-related encephalopathies, including scrapie and bovine spongiform encephalopathy in livestock and Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, and kuru in humans, are neurodegenerative disorders characterized by early synaptic loss, astrocytosis, progressive neuronal loss, and often cerebral protein aggregation and deposition (Gajdusek et al., 1966;Clinton et al., 1993;Fraser, 1993;Jeffrey et al., 1994). These diseases appear to be caused by the posttranslational and conformational transition of the normal cellular prion protein (PrP) isoform, PrP C , into the abnormal and pathogenic PrP isoform, PrP SC (Prusiner, 1982(Prusiner, , 1991Hope and Manson, 1991). Fourier transform infrared spectroscopy and circular dichroism (CD) demonstrate that PrP C is predominantly ␣-helical (42%) with little ␤-sheet structure (3%). However, the protease-resistant core of PrP SC is mostly ␤-sheet (43%) with less ␣-helical structure (30%), and it has a tendency to polymerize into amyloid fibrils (Prusiner et al., 1983;Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994). Based on these structural measurements, researchers have postulated that PrP SC formation involves a conformational transformation resulting in increased ␤-sheet content (Pan et al., 1993;Safar et al., 1993;Baldwin et al., 1994).Structural changes similar to the PrP C to PrP SC conformational conversion associated with prion diseases ar...

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Scrapie prions aggregate to form amyloid-like birefringent rods

Cited by 1,007 publications

References 48 publications

Metal‐dependent α‐helix formation promoted by the glycine‐rich octapeptide region of prion protein

Metal‐dependent α‐helix formation promoted by the glycine‐rich octapeptide region of prion protein

Mass spectrometric detection of attomole amounts of the prion protein by nanoLC/MS/MS

The Role of Prion Peptide Structure and Aggregation in Toxicity and Membrane Binding

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