title: Human prions and plasma lipoproteins.
abstract: 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 degrees 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.
authors.affiliation: Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.forename: Holger
authors.initials: H
authors.lastname: Wille
authors.forename: Michael D
authors.initials: MD
authors.lastname: Geschwind
authors.forename: Camille
authors.initials: C
authors.lastname: Deering
authors.forename: Diane
authors.initials: D
authors.lastname: Latawiec
authors.forename: Ana
authors.initials: A
authors.lastname: Serban
authors.forename: David J
authors.initials: DJ
authors.lastname: King
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Karl H
authors.initials: KH
authors.lastname: Weisgraber
authors.forename: Robert W
authors.initials: RW
authors.lastname: Mahley
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Dearmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019791:Guanidine / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry; D008075:Lipoproteins, HDL / Q000737:chemistry; D008077:Lipoproteins, LDL / Q000737:chemistry; D008079:Lipoproteins, VLDL / Q000737:chemistry; D010772:Phosphotungstic Acid / Q000494:pharmacology; D011328:Prions / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013696:Temperature
chemical_list: D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011328:Prions; D011994:Recombinant Proteins; D010772:Phosphotungstic Acid; D019791:Guanidine