Voderholzer, D. | bioRxiv Science

bioRxiv2025

Self-consistent analytical solutions to the kinetics of lipid-induced protein aggregation

The aggregation of proteins into amyloid fibrils is a hallmark of several neurodegenerative disorders, including Parkinsons disease. A growing body of experimental evidence highlights the significant role lipid membranes play in modulating this aggregation process, particularly for proteins such as -synuclein. Despite this, there has been a lack of quantitative theoretical frameworks capable of describing the kinetics of lipid-induced protein aggregation. In this work, we develop an analytical model that explicitly incorporates lipid-mediated interactions into the aggregation kinetics. By formulating rate equations in terms of lipid surface coverage and applying a fixed-point analysis, we derive self-consistent solutions for the full timecourse of aggregation. Our model captures both one-step and two-step nucleation mechanisms and enables the prediction of key kinetic observables, including half-times and maximal growth rates. These results provide a quantitative foundation for interpreting experimental data and offer new mechanistic insights into how lipids influence the self-assembly of amyloidogenic proteins.

biophysics↗

bioRxiv2024

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

The aggregation of -synuclein into amyloid fibrils is a hallmark of Parkinsons 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 -synuclein. Using this framework we find that -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 -synuclein aggregation, finding that this small molecule reduces the rate of lipid-dependent primary nucleation. Our work will likely guide the rational design of -synuclein aggregation inhibitors. Significance StatementAmyloid aggregation is a hallmark of a diverse range of diseases including Parkinsons Disease, where the protein -synuclein is a major con-stituent of proteinaceous deposits found in patients. It is well established that interactions between -synuclein and lipids modulate aggregation. However, the molecular mechanisms driving this lipid-induced aggregation have remained largely elusive, which has frustrated so far the discovery of drugs that prevent lipid-induced aggregation. In this work, we present the first global kinetic model describing lipid-induced aggregation and by integrating this theoretical framework with in vitro experimental data of lipid-induced -synuclein aggregation, we reveal the role of lipid membranes in the aggregation process and uncover the mechanism by which small molecule inhibitors interfere with this process.

biophysics↗