Fitting neurological protein aggregation kinetic data via a 2-step, minimal/"Ockham's razor" model: the Finke-Watzky mechanism of nucleation followed by autocatalytic surface growth.

摘要: The aggregation of proteins has been hypothesized to be an underlying cause many neurological disorders including Alzheimer's, Parkinson's, and Huntington's diseases; protein is also important normal life function in cases such as G F-actin, glutamate dehydrogenase, tubulin flagella formation. For this reason, the mechanism aggregation, accompanying kinetic models for nucleation growth (growth being called elongation, polymerization, or fibrillation literature), have investigated more than 50 years. As a way concisely present key prior literature area, Table 1 main text summarizes 23 papers by 10 groups authors that provide 5 basic classes mechanisms over period from 1959 2007. However, despite major effort, still lacking are both (i) anything approaching consensus (or mechanisms), (ii) generally useful, thus widely used, simplest/"Ockham's razor" model associated equations can routinely employed analyze broader range data. Herein we demonstrate 1997 Finke-Watzky (F-W) 2-step slow continuous nucleation, A --> B (rate constant k1), followed typically fast, autocatalytic surface growth, + 2B k2), able quantitatively account curves all 14 representative data sets found search (the prion was largely excluded purposes study order some limit resultant covered). F-W deconvolute desired k1, k2, rate constants those obtained four different physical methods, three proteins, nine labs. fits good, excellent, with R2 values >or=0.98 cases. such, contribution current record widest set best fit what simplest offered date. Also provided mathematical connection between 2000 3-step proposed Saito co-workers. In particular, equation Saito's shown mathematically identical earlier, under 3 simplifying assumptions co-workers used derive their equation. list caveats/limitations provided, conclusions well needed future experiments.