Figure 1.

Initiation of polyQ aggregation according to the nucleated growth polymerization model suggested by Wetzel et al. (36,37,62). The model considers that the nonaggregating monomer ensemble M is in preequilibrium with the free-energetically most unfavorable state along the aggregation pathway (state 1), in which monomers are found in a conformation capable of initiating aggregation (36). For pathological-length polyQ, the population ratio between the states M and 1 is estimated to be of the order of 1,000,000,000:1 (63). Notably, due to asymmetric exit rates (k₋₁ > k₊[M], indicated by the length and thickness of arrows), a peptide in state 1 would still be much more likely to go to state M than to state 2 (37). From state n ≥ 2, the state n + 1 is more likely than state n – 1. As the monomer concentration [M] is initially effectively constant, we depict all the reactions as first-order, with the (second-order) growth reaction taking place with a pseudo-first-order reaction rate k₊[M].