Ganglioside lipids accelerate α-synuclein amyloid formation

Abstract

The deposition of α-synuclein fibrils is one hallmark of Parkinson's disease. Here, we investigate how ganglioside lipids, present in high amounts in neurons and exosomes, influence the aggregation kinetics of α-synuclein. Gangliosides, as well as, other anionic lipid species with small or large headgroups were found to induce conformational changes of α-synuclein monomers and catalyse their aggregation at mildly acidic conditions. Although the extent of this catalytic effect was slightly higher for gangliosides, the results imply that charge interactions are more important than headgroup chemistry in triggering aggregation. In support of this idea, uncharged lipids with large headgroups were not found to induce any conformational change and only weakly catalyse aggregation. Intriguingly, aggregation was also triggered by free ganglioside headgroups, while these caused no conformational change of α-synuclein monomers. Our data reveal that partially folded α-synuclein helical intermediates are not required species in triggering of α-synuclein aggregation.

Self-Assembly in Ganglioside‒Phospholipid Systems: The Co-Existence of Vesicles, Micelles, and Discs

“…The mildly acidic pH is relevant to some cellular environments, such as endosomes and lysosomes. At these conditions, ganglioside-containing membranes have also been shown to trigger the aggregation of the amyloid protein α-synuclein, which is associated with Parkinson's disease [8,36]. For practical reasons, the overall lipid concentration varies between experiments using different methods, so an overview of the concentrations and molar ratios in all samples investigated is given in Table 1.…”

“…In relation to the example highlighted in the introduction, that ganglioside-containing lipid systems can cause an acceleration in the amyloid aggregation of α-synuclein, we can speculate on some aspects of the system that may indeed influence the interaction between this protein and the lipid assemblies. It has been shown that α-synuclein adsorbs to lipid membranes and micelles with a negative charge [36,[75][76][77]. In the adsorbed state, the protein forms an α-helix at the membrane/micelle interface [36,75,78], and membranes covered with proteins are also a trigger for the aggregation process [36,75].…”

“…It has been shown that α-synuclein adsorbs to lipid membranes and micelles with a negative charge [36,[75][76][77]. In the adsorbed state, the protein forms an α-helix at the membrane/micelle interface [36,75,78], and membranes covered with proteins are also a trigger for the aggregation process [36,75]. Here, the mode of binding strongly depends on the size and curvature of the lipid assembly: a broken helix is formed for micelles, while for large vesicles the helix is unbroken [79,80].…”

“…Here, the mode of binding strongly depends on the size and curvature of the lipid assembly: a broken helix is formed for micelles, while for large vesicles the helix is unbroken [79,80]. In a system with co-existing highly charged micelles and planar membranes with low surface charge density, one can foresee an exchange between different protein conformational states, which may also impact the nucleation and aggregation process [36,75,81]. Furthermore, the protein aggregation process strongly depends on the relationship between protein concentration and the total area of charged lipid membranes available [36,75].…”

“…In a system with co-existing highly charged micelles and planar membranes with low surface charge density, one can foresee an exchange between different protein conformational states, which may also impact the nucleation and aggregation process [36,75,81]. Furthermore, the protein aggregation process strongly depends on the relationship between protein concentration and the total area of charged lipid membranes available [36,75]. Disease-related changes in the content and compositions of gangliosides [9,82,83] may therefore affect protein aggregation processes and the formation of amyloid deposits.…”