NR AUZS
AU Safar,J.G.; Wille,H.; Geschwind,M.D.; Deering,C.; Latawiec,D.; Serban,A.; King,D.J.; Legname,G.; Weisgraber,K.H.; Mahley,R.W.; Miller,B.L.; DeArmond,S.J.; Prusiner,S.B.
TI Human prions and plasma lipoproteins
QU Proceedings of the National Academy of Sciences of the United States of America 2006 Jul 25; 103(30): 11312-7
IA http://www.pnas.org/cgi/content/full/103/30/11312
PT journal article
AB Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrPsc. The polyoxometalate phosphotungstic acid has been used to separate PrPsc from its precursor PrPc by selective precipitation; notably, native PrPsc has not been solubilized by using nondenaturing detergents. Because of the similarities between PrPsc 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 PrPsc through a highly cooperative process. Approximately 50% of the PrPsc 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) PrPsc or denatured recombinant HuPrP(90-231) for apoB and LDL ranged from 28 to 212 pM. Whether detection of PrPsc 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.
MH Brain/metabolism; Dose-Response Relationship, Drug; Guanidine/pharmacology; Humans; Kinetics; Lipoproteins/*blood/chemistry; Lipoproteins, HDL/chemistry; Lipoproteins, LDL/chemistry; Lipoproteins, VLDL/chemistry; Phosphotungstic Acid/pharmacology; Prions/chemistry/*physiology; Recombinant Proteins/pharmacology; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Temperature
AD Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA
SP englisch
PO USA