Global kinetic model of lipid-induced a-synuclein aggregation and its inhibition by small molecules

• 成果类型: Article
• 署名作者: Stevenson, Alisdair; Staats, Roxine; Dear, Alexander J.; Voderholzer, David; Dreier, Jesper E.; Meisl, Georg; Guido, Raphael; Knowles, Tuomas P. J.; Galvagnion, Celine; Buell, Alexander K.; Vendruscolo, Michele; Michaels, Thomas C. T.
• 署名单位: Swiss Federal Institutes of Technology Domain; ETH Zurich; Swiss Federal Institutes of Technology Domain; ETH Zurich; University of Cambridge; University of Copenhagen; Technical University of Denmark
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10335
• DOI: 10.1073/pnas.2422427122
• 发表日期: 2025-06-25
• 关键词: alpha-synuclein; parkinsons-disease; macroscopic measurements; microscopic mechanisms; nucleation; polymerization; initiation; oligomers; toxicity; crystals

摘要

The aggregation of a-synuclein into amyloid fibrils is a hallmark of Parkinson's disease. This process has been shown to directly involve interactions between proteins and lipid surfaces when the latter are present. Despite this importance, the molecular mechanisms of lipid-induced amyloid aggregation have remained largely elusive. Here, we present a global kinetic model to describe lipid-induced amyloid aggregation of a-synuclein. Using this framework, we find that a-synuclein fibrils form via a two-step primary nucleation mechanism and that lipid molecules are directly involved in both the nucleation and fibril elongation steps, giving rise to lipid-protein coaggregates. To illustrate the applicability of this kinetic approach to drug discovery, we identify the mechanism of action of squalamine, a known inhibitor of lipid-induced a-synuclein aggregation, revealing that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design of a-synuclein aggregation inhibitors.