NR AWMI
AU Prusiner,S.B.
TI Synthetic prion strains 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 - Oral sessions ORAL-20
PT Konferenz-Vortrag
AB How PrPsc enciphers the information required to direct the replication of one isolate from a large ensemble of different strains is unknown; moreover, the biophysical explanation for the unprecedented plasticity of PrPsc presents a perplexing conundrum. Using synthetic prion strains formed initially from recombinant MoPrP(89-230) that was polymerized into amyloid, we investigated conformational stability as a function of incubation time in mice. The stability of prion isolates was determined by the GdnHCl concentration required to denature 50% of the PrPsc molecules, denoted [GdnHCl]1/2. When incubation times were plotted as a function of the [GdnHCl]1/2 values for 30 prion isolates from synthetic and naturally occurring sources, a linear relationship was found with a correlation coefficient of 0.93. These findings demonstrate that (i) less stable prions replicate more rapidly than do stable prions and (ii) a continuum of PrPsc structural states enciphers a multitude of incubation-time phenotypes. In other investigations, the similarities between PrPsc and lipoproteins with respect to hydrophobicity and complex formation with phosphotungstic acid led us to perform binding studies. Prions from patients with sporadic Creutzfeldt-Jakob disease bound to VLDL and LDL but not to HDL or other plasma components. Apolipoprotein B (apoB), which is the major protein component of VLDL and LDL, bound PrPsc through a highly cooperative process. The apparent binding constants of native human PrPsc 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.
AD Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, USA. E-mail: stanley@ind.ucsf.edu
SP englisch
PO Italien