Binding of disease-associated prion protein to plasminogen

Fischer, Michael B.; Roeckl, Christiane; Parizek, Petra; Schwarz, Hans; Aguzzi, Adriano

doi:10.1038/35044100

Cited by 203 publications

(139 citation statements)

References 19 publications

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“…supported by experiments showing that FabЈ fragments of some of these antibodies failed to immunoprecipitate PrPsc. This is not surprising taking into account that several proteins and polymers have already been shown to bind SAFs, including serum proteins (12), heparan sulfates (13,14), and nucleic acids (4,15). In addition, we show that a significant PrPsc immunoprecipitation can be obtained even with BSA-coated beads in appropriate conditions.…”

Section: Discussionsupporting

confidence: 71%

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Morel

Simon

Frobert

et al. 2004

Journal of Biological Chemistry

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Transmissible spongiform encephalopathies are characterized by the accumulation in brain tissues of an abnormal isoform of the prion protein named PrPsc, which is the only direct marker known for transmissible spongiform encephalopathies. Here we show that PrPsc can be specifically immunoprecipitated by using several monoclonal antibodies (mAbs) of various specificities independently of the properties of their binding site (paratope). These results strongly suggest that a significant proportion of mAbs can interact with PrPsc aggregates through nonspecific paratope-independent interactions allowing selective immunoprecipitation of PrPsc when these mAbs are immobilized on a polydisperse solid phase like microbeads.

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Section: Discussionsupporting

confidence: 71%

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Morel

Simon

Frobert

et al. 2004

Journal of Biological Chemistry

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“…Improved diagnostic tests could now be developed using a new cyclic amplification procedure, which is capable of efficiently amplifying minute amounts of PrP Sc in brain tissue (37). Coupled with a reagent that specifically binds to PrP Sc , such as the recently identified plasminogen (38), this might reveal the levels of prion infectivity looming in the blood.…”

Section: Discussionmentioning

confidence: 99%

Similar Turnover and Shedding of the Cellular Prion Protein in Primary Lymphoid and Neuronal Cells

Parizek¹,

Roeckl²,

Weber³

et al. 2001

Journal of Biological Chemistry

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The cellular prion protein (PrP C ) is essential for pathogenesis and transmission of prion diseases. Although prion replication in the brain is accompanied by neurodegeneration, prions multiply efficiently in the lymphoreticular system without any detectable pathology. We have used pulse-chase metabolic radiolabeling experiments to investigate the turnover and processing of PrP C in primary cell cultures derived from lymphoid and nervous tissues. Similar kinetics of PrP C degradation were observed in these tissues. This indicates that the differences between these two organs with respect to their capacity to replicate prions is not due to differences in the turnover of PrP C . Substantial amounts of a soluble form of PrP that lacks the glycolipid anchor appeared in the medium of splenocytes and cerebellar granule cells. Soluble PrP was detected in murine and human serum, suggesting that it might be of physiological relevance.

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“…Other investigators reported mouse Rocky Mountain Laboratory (RML) prions bind to plasminogen (38), but subsequent studies by others demonstrated that the affinity of PrP for plasminogen is low (M. Vey, personal communication; see ref. 39).…”

Section: Prions In Bloodmentioning

confidence: 99%

Human prions and plasma lipoproteins

Safar

Wille

Geschwind

et al. 2006

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

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Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrP Sc . The polyoxometalate phosphotungstic acid has been used to separate PrP Sc from its precursor PrP C by selective precipitation; notably, native PrP Sc has not been solubilized by using nondenaturing detergents. Because of the similarities between PrP Sc and lipoproteins with respect to hydrophobicity and formation of phosphotungstic acid complexes, we asked whether these molecules are bound to each other in blood. Here we report that prions from the brains of patients with sporadic Creutzfeldt-Jakob disease (CJD) bind to very low-density (VLDL) and low-density (LDL) lipoproteins but not to high-density lipoproteins (HDL) or other plasma components, as demonstrated both by affinity assay and electron microscopy. Immunoassays demonstrated that apolipoprotein B (apoB), which is the major protein component of VLDL and LDL, bound PrP Sc through a highly cooperative process. Approximately 50% of the PrP Sc bound to LDL particles was released after exposure to 4 M guanidine hydrochloride at 80°C for 20 min. The apparent binding constants of native human (Hu) PrP Sc or denatured recombinant HuPrP(90 -231) for apoB and LDL ranged from 28 to 212 pM. Whether detection of PrP Sc in VLDL and LDL particles can be adapted into an antemortem diagnostic test for prions in the blood of humans, livestock, and free-ranging cervids remains to be determined. prion protein ͉ apolipoprotein B ͉ blood ͉ Creutzfeldt-Jakob disease P rions are composed solely of an alternatively folded isoform of the prion protein, designated PrP Sc . Despite numerous efforts to solubilize native PrP Sc , no procedure has been developed except for incorporation of the protein into liposomes (1, 2). The hydrophobic properties of PrP Sc not only have impeded biological investigations but also have prevented structural studies at atomic resolution.During the development of an immunoassay for PrP Sc that does not depend upon limited proteolysis to hydrolyze the precursor protein designated PrP C , we found that the Na salt of phosphotungstic acid (PTA) selectively complexes with PrP Sc (3). PTA is a water-soluble salt featuring the nearly spherical trianion [PW 12 O 14 ] 3Ϫ that belongs to a broad class of polynuclear transition metal-oxo complexes known as polyoxometalates (POMs; see ref. 4). Recently, two of us (J.G.S. and S.B.P.) investigated the mechanism of selective complex formation between Keggin-type POMs and PrP Sc using a series of POM analogues (5). The ability of POMs to complex with PrP Sc as well as lipoproteins (6) raised the possibility that these two hydrophobic proteins might copurify.We began by examining the distribution of human (Hu) PrP Sc in human plasma fractions spiked with sporadic CreutzfeldtJakob disease (sCJD) prions from human brain. CJD prions were found with very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) but not with high-density lipoproteins (HDL) or any other plasma component. In addition to b...

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Binding of disease-associated prion protein to plasminogen

Cited by 203 publications

References 19 publications

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Selective and Efficient Immunoprecipitation of the Disease-associated Form of the Prion Protein Can Be Mediated by Nonspecific Interactions between Monoclonal Antibodies and Scrapie-associated Fibrils

Similar Turnover and Shedding of the Cellular Prion Protein in Primary Lymphoid and Neuronal Cells

Human prions and plasma lipoproteins

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