N‑Terminal Acetylation Affects α‑Synuclein Fibril Polymorphism

• Published in: Biochemistry (Easton) Vol. 58; no. 35; pp. 3630 - 3633
• Main Authors: Watson, Matthew D, Lee, Jennifer C
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 03-09-2019
• Subjects: Acetylation; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Amyloid - chemistry; Amyloid - genetics; Amyloid - metabolism; Amyloidogenic Proteins - genetics; Amyloidogenic Proteins - metabolism; Humans; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Polymorphism, Genetic; Protein Aggregation, Pathological - genetics; Protein Aggregation, Pathological - metabolism; Protein Domains; Protein Processing, Post-Translational - physiology; Protein Structure, Secondary - genetics
• ISSN: 0006-2960; 1520-4995
• DOI: 10.1021/acs.biochem.9b00629

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.