N-Terminal Acetylation Affects ?-Synuclein Fibril Polymorphism.

ABSTRACT: Parkinson's disease etiology involves amyloid formation by ?-synuclein (?Syn). In vivo, ?Syn is constitutively acetylated at the ?-amino N-terminus. Here, we find N-terminally acetylated ?Syn (Ac-?Syn) aggregates more slowly than non-acetylated ?Syn (NH3-?Syn) 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-?Syn fibrils seed both acetylated and non-acetylated ?Syn and faithfully propagate the low-ThT character through several generations, indicating a stable fibril polymorph. In contrast, the high-ThT NH3-?Syn seeds lose fidelity over subsequent generations. Despite it being outside of the amyloid core, the chemical nature of the N-terminus modulates ?Syn aggregation and fibril polymorphism.

SUBMITTER: Watson MD 

PROVIDER: S-EPMC6721997 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature