Molecular mechanism of α-synuclein aggregation on lipid membranes revealed

Dear, Alexander J.; Teng, Xiangyu; Ball, Sarah R.; Lewin, Joshua; Horne, Robert I.; Clow, Daniel; Stevenson, Alisdair; Harper, Natasha; Yahya, Kim; Yang, Xiaoting; Brewerton, Suzanne C.; Thomson, John; Michaels, Thomas C. T.; Linse, Sara; Knowles, Tuomas P. J.; Habchi, Johnny; Meisl, Georg

doi:10.1039/d3sc05661a

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2024

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Cited by 3 publications

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Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

Makasewicz,

Carlström,

Stenström

et al. 2024

Cell Reports Physical Science

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Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

Makasewicz,

Carlström,

Stenström

et al. 2024

Cell Reports Physical Science

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

Stevenson,

Staats,

Dear

et al. 2024

Preprint

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The aggregation of alpha-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 alpha-synuclein. Using this framework we find that alpha-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 alpha-synuclein aggregation, finding that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design of alpha-synuclein aggregation inhibitors.

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Lipids and α-Synuclein: adding further variables to the equation

Schepers,

Löser,

Behl

2024

Front. Mol. Biosci.

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Molecular mechanism of α-synuclein aggregation on lipid membranes revealed

Abstract: Lipids are an important factor in the disease-associated aggregation of α-synuclein. Here we develop a kinetic model that allows the determination of mechanistic details and rate constants of this process.

Cited by 3 publications

References 62 publications

Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

Tipping point in α-synuclein-membrane interactions from stable protein-covered vesicles to amyloid aggregation

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

Lipids and α-Synuclein: adding further variables to the equation

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