The Formation of Higher Order Structures by the Neuronal Protein Alpha-Synuclein: Self-Assembly Over Multiple Length Scales

19 in the CHR significantly affected the aggregation rate. This is seen as an extended half-time and steeper concentration dependence suggesting a change in aggregation mechanism relative to the wild type protein. We also studied co-aggregation and cross-seeding between the kinetically faster Ab42 and the slower Ab40. The aggregation process starting from mixed monomers displays two transitions and our data imply that there is cross-reactivity between Ab40 and Ab42 at the level of primary nucleation only, while fibril elongation and surface-catalysed secondary nucleation are highly specific events. In contrast, co-aggregation of Ab42 with the slower mutant F19L only displays a single sigmoidal transition and the cross-seeding is as efficient as the self-seeding. The main reason for the discrimination in the different pathways is the length at the C-terminus rather than the difference in intrinsic aggregation rates. To further investigate the relative role of intermolecular interactions we changed the temperature to provide information on energy barriers and their enthalpic and entropic components. With an analytically solved model we could do a global fitting to estimate the activation energy for Ab42 for the primary nucleation, secondary nucleation and elongation.