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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

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N-Terminal Acetylation Affects α-Synuclein Fibril Polymorphism.

Watson Matthew D MD Lee Jennifer C JC

Biochemistry 20190821 35

Parkinson's disease etiology involves amyloid formation by α-synuclein (αSyn). <i>In vivo</i>, 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 (NH<sub>3</sub>-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 ...[more]

PMID: 31424918

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