Abstract
Meisl et al. have recently observed an anomalous dependence of the amyloid formation rate on the protein concentration. A novel mechanism of fibril growth has been proposed by Meisl et al. to explain the abnormality; it consists in the fibril-catalyzed initiation of fibril formation with saturation of catalytic sites at high concentrations of substrates. Our article describes an alternative explanation of the anomalous kinetics, assuming that the formation of metastable oligomers competes with fibril formation by decreasing the concentration of free monomers. Oligomers are indeed observed in the course of amyloid formation, but are usually considered as seeds of amyloid fibrils rather as their competitors. However, the oligomers visually detectable by electron microscopy were shown to be close in size to those that can be derived from the anomalous dependence of the amyloid growth rate on the protein concentration, given that the anomaly results from competition between oligomer formation and amyloidogenesis.
Highlights
The formation of amyloid fibrils underlies many fatal disorders, such as Alzheimer’s and Huntington’s diseases [1]
Some of the scenarios proposed for fibril formation include a primary nucleation of fibrils by seeds consisting of monomers, and a secondary nucleation, wherein new fibrils are initiated via fragmentation or bifurcation of the existing ones (Fig. 1)
We propose an alternative possible explanation of the observed anomalous kinetics, assuming that the formation of metastable oligomers competes with fibril formation by absorbing a part of proteins yet uninvolved in fibrils and thereby decreasing the concentration of free fibril-forming monomers and, the rate of fibril formation
Summary
The formation of amyloid fibrils underlies many fatal disorders, such as Alzheimer’s and Huntington’s diseases [1]. To estimate the amyloid formation half-time t1/2, Eq (1) should be considered for a relatively low polymerized monomer concentration [Pn]
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