NR AWMX
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 Prion clearance and plasma lipoproteins
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PA-47
PT Konferenz-Poster
AB Prions are composed solely of an alternatively folded isoform of the prion protein (PrP), designated PrPsc. The half-life (t1/2) of PrPsc in the mouse brain is ~1.5 days and both protease-sensitive (s) and resistant (r) conformers are cleared at the same rate. That the brain is capable of clearing prions so efficiently raises the possibility that PrPsc is normally made at low levels and continually cleared; thus, PrPsc may have a function in cellular metabolism; furthermore, this clearance mechanism improves prospects for effective therapy. Because such rapid clearance implies a powerful transport mechanism, we aimed to identify the proteins in plasma that bind and may carry prions from the brain. The similarities between PrPsc and plasma lipoproteins with respect to hydrophobicity and formation of polyoxometalate phosphotungstic acid (PTA) complexes led us to investigate whether these molecules bind to each other in human plasma. We found that prions from the brains of patients with sporadic Creutzfeldt-Jakob disease (sCJD) bind to very low-density and low-density lipoproteins (VLDL and LDL, respectively) but not to high-density lipoproteins (HDL) or other plasma components, as demonstrated by affinity assay and electron microscopy. Immunoassays showed that apolipoprotein B (apoB), which is the principal protein component of VLDL and LDL, also bound native PrPsc through a highly cooperative process; the apparent binding constants ranged from 28 to 212 pM. Furthermore, HuPrPsc was detected in VLDL and LDL fractions, but not in the HDL or immunoglobulin fractions, of plasma collected from sCJD patients. These findings suggest that binding of human prions to plasma VLDL and LDL is an important factor in prion propagation. Whether detection of PrPsc in VLDL and LDL particles can be adapted into an antemortem diagnostic test for prions in the blood remains to be determined.
AD J.G. Safar, H. Wille, G. Legname: Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA; M.D. Geschwind, B.L. Miller: Department of Neurology, University of California, San Francisco, CA 94143, USA; C. Deering, D. Latawiec, A. Serban, D.J. King: Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143; USA; K.H. Weisgraber, R.W. Mahley: Gladstone Institute, University of California, San Francisco, CA 94143, USA; S.J. DeArmond: Institute for Neurodegenerative Diseases, Department of Pathology, University of California, San Francisco, CA 94143, USA; S.B. Prusiner: Institute for Neurodegenerative Diseases, Departments of Neurology, Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA
SP englisch
PO Italien