N-Terminal Acetylation Affects α-Synuclein Fibril Polymorphism

Parkinson’s disease etiology involves amyloid formation by α-synuclein (αSyn). In vivo, αSyn is constitutively acetylated at the α-amino N-terminus. Here, we find N-terminally acetylated αSyn (Ac-αSyn) aggregates more slowly than non-acetylated αSyn (NH3-αSyn) with significantly reduced sensitivity to thioflavin T (ThT). Fibril differences were characterized by transmission electron microscopy, circular dichroism spectroscopy, and limited proteolysis. Interestingly, the low-ThT Ac-αSyn fibrils seed both acetylated and non-acetylated αSyn and faithfully propagate the low-ThT character through several generations, indicating a stable fibril polymorph. In contrast, the high-ThT NH3-αSyn seeds lose fidelity over subsequent generations. Despite it being outside of the amyloid core, the chemical nature of the N-terminus modulates αSyn aggregation and fibril polymorphism.