NR AXZM
AU Yousefi,M.; Taghibiglou,C.; Yanai,A.; Cashman,N.R.
TI Mathematical Modeling for Prion Propagation
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.51
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Prions are proteinaceous agents that cause the transmissible spongiform encephalopathies (TSE), affecting both animals and humans. Prions consist largely, if not entirely, of a misfolded, host-encoded glycoprotein designated PrP (prion protein). There are several theories that model prion replication mainly focusing on conversion of the normal cellular protein (PrPc) to a misfolded pathogenic form (PrPsc) followed by aggregated fibril formation. Here we consider the nucleated polymerization model and simulate molecular reactions by modifying previously reported estimations for reaction rates (Rubenstein et al, Biophysical Chemistry, 2006) to investigate dynamic behavior of this model in a neuronal cell. Gillespie-Direct discrete event simulator has been applied on a prion propagation model based on ordinary differential equations.
PrPc is an abundant protein in neuronal cells, and in the present model initial PrPc concentration was modified to 50,000 molecules per cell, according to our previous observations (Cashman et al, Cell 1990; Cashman, unpublished). Monte Carlo simulation of the nucleated polymerization model result shows a rapid decrease of PrPc to 600 molecules in the first two days and a smooth slope to steady state after 70 days. Experimental data from our lab demonstrates a decrease of cell surface prion protein immunoreactivity, consistent with this modeling prediction (Griffin et al, NeuroReport, 2007).
Half lives are around 4 hours for PrPc and more than two days for PrPsc, corresponding with published experimental data ( Caughey, Adv. Protein Chem. 2001). By adjusting the model parameters and retaining the same slope, PrPsc concentration increased and PrPsc aggregates formed much earlier than previously reported.
Here, as part of an ongoing project, we present a mathematical modeling, that covers both experimental and simulation approaches in prion disease research.
AD M. Yousefi, C. Taghibiglou, A. Yanai, N.R. Cashman, University of British Columbia, Brain Research Centre, Canada
SP englisch
PO Schottland