The abnormal aggregation of α-synuclein (α-Syn) is closely associated with Parkinson's disease. Different post-translational modifications of α-Syn have been identified and contribute distinctly in α-Syn aggregation and cytotoxicity. Recently, α-Syn was reported to be N-terminally acetylated in cells, yet the functional implication of this modification, especially in α-Syn oligomerization, remains unclear. By using a solid-state nanopore system, we found that N-terminal acetylation can significantly decrease α-Syn oligomerization. Replica-exchange molecular dynamics simulations further revealed that addition of an acetyl group at the N-terminus disrupts intermolecular hydrogen bonds, which slows down the initial α-Syn oligomerization. Our finding highlights the essential role of N-terminal acetylation of α-Syn in preserving its native conformation against pathological aggregation.
Keywords: N-terminal acetylation; Parkinson’s disease oligomerization; α-Synuclein.