Study of Molecular Mechanisms of α‑SynucleinAssembly: Insight into a Cross‑βStructure in the N‑Termini of New α‑SynucleinFibrils

Parkinson’s disease is characterized by the self-assembly of α-synuclein (AS), in which its aggregates accumulate in the substantia nigra. The molecular mechanisms of the self-assembly of AS are challenging because AS is a relatively large intrinsically disordered protein, consisting of 140 residues. It is known that the N-termini of AS contribute to the toxicity of the proteins; therefore, it is important to investigate the self-assembly structure of the N-termini on AS as well. There have been extensive efforts to investigate the structural fibrils of AS(1–140), which have shown that the N-termini are disordered and do not participate in the fibrillary structure. This study illustrates for the first time that the N-termini of AS play a crucial role in the self-assembly of AS. This study reveals a new structure of AS(1–140) fibrils, in which the N-termini are essential parts of the cross-β structure of the fibrillary structure. This study suggests that there are polymorphic states of the self-assembled A...