2003/07/09 by David L. Mobley, Daniel L. Cox, Rajiv R. P. Singh +3 · 1 citation
Biochemistry, Genetics and Molecular Biology · Medicine · Physics and Astronomy · #Diffusion and Search Dynamics #Mathematical and Theoretical Epidemiology and Ecology Models #Prion Diseases and Protein Misfolding #physics.bio-ph #physics.comp-ph #q-bio.BM
paper · pdf · doi:10.1016/s0006-3495(03)74647-5
published as Biophys. J. 85:2213-2223 (Oct. 2003) · 8 pages, 10 figures For larger versions of several figures, see http://asaph.ucdavis.edu/~dmobley and click on the prion paper link
arxiv created 2003/07/09 · openalex publication_date 2003/10/01 · arxiv updated 2009/12/01 · openalex created_date 2016/06/24 · openalex updated_date 2026/08/01
We extend our previous stochastic cellular automata based model for areal aggregation of prion proteins on neuronal surfaces. The new anisotropic model allow us to simulate both strong beta-sheet and weaker attachment bonds between proteins. Constraining binding directions allows us to generate aggregate structures with the hexagonal lattice symmetry found in recently observed in vitro experiments. We argue that these constraints on rules may correspond to underlying steric constraints on the aggregation process. We find that monomer dominated growth of the areal aggregate is too slow to account for some observed doubling time-to-incubation time ratios inferred from data, and so consider aggregation dominated by relatively stable but non-infectious oligomeric intermediates. We compare a kinetic theory analysis of oligomeric aggregation to spatially explicit simulations of the process. We find that with suitable rules for misfolding of oligomers, possibly due to water exclusion by the surrounding aggregate, the resulting oligomeric aggregation model maps onto our previous monomer aggregation model. Therefore it can produce some of the same attractive features for the description of prion incubation time data. We propose experiments to test the oligomeric aggregation model.