Model establishes framework for designing drugs to prevent neurodegenerative disorders

Many neurodegenerative disorders, such as Parkinson’s disease, share the hallmark of functional proteins forming deposits known as amyloid fibrils in a process that can be modulated by the presence of lipids. To date, there has been a lack of quantitative theoretical frameworks that describe this lipid-induced protein aggregation.

Stevenson et al. developed a theoretical model of lipid-induced aggregation with the aim of creating a tool that can be used to inform the design of anti-aggregation drugs. The analytical model accounts for lipid-mediated interactions in terms of kinetic equations for the surface coverage of monomers and aggregates. Analytical self-consistent solutions are found for the equations that are useful for interpreting experimental data.

“Our results mean that there is now a robust framework to analyze experimental data of aggregation kinetics exploring the critical links between lipids and amyloidogenic proteins, providing a way to link experimental data to microscopic aggregation mechanisms,” said author Alisdair Stevenson.

The authors utilized the framework to reveal that α-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 co-aggregates.

“This is critical information for designing inhibitors against pathogenic aggregation, because it tells us which kinetically dominant pathways of aggregation should be specifically targeted,” Stevenson said. “Moving forward, we are using our framework to rationalize the effects of lipid-induced aggregation inhibitors, and we hope other research groups will apply it to study different amyloidogenic proteins such as islet amyloid polypeptide and amyloid-β.”

Source: “Self-consistent analytical solutions to the kinetics of lipid-induced protein aggregation,” by Alisdair Stevenson, David Voderholzer, and Thomas C. T. Michaels, Journal of Chemical Physics (2025). The article can be accessed at https://doi.org/10.1063/5.0279601 .