Figure 2

Proposed models for the aggregation pathway. a Established schematic view for the pathway of aggregation of natively unfolded proteins [40]. According to this model, from an unfolded protein (U_N) is formed an intermediate (I), which further aggregates into protofibrils (P) and eventually into fibrils (F). b The extended model we propose takes into account the possibility that a population of strains are produced, together with off-pathway oligomers that do not show the ability to form α-synuclein fibrils. Intermediate forms marked as I₁ to I_n, each of them may produce a different protofibrillar form, marked as P_1-n to P_n-n (the protofibril P₁ derived from the intermediate I₁ until the protofibril P_n derived from the intermediate I_n). It is noteworthy to state that the process may be in equilibrium between the aggregation of the intermediates and the rupture of protofibrillar forms. Further aggregation will cause the collapse into a limited number of fibrillar structures