Ganglioside GM3 stimulates lipid-protein co-assembly in ?-synuclein amyloid formation

Parkinson's disease is characterized by the aggregation of the presynaptic protein alpha-synuclein (alpha Syn), and its co -assembly with lipids and other cellular matter in the brain. Here we investigated lipid-protein co-assembly in a system composed of alpha Syn and model membranes containing the glycolipid ganglioside GM3. We quantified the uptake of lipids into the co-assembled aggregates and investigated how lipid molecular dynamics is altered by being present in the co-assemblies using solution 1H-and solid-state 13C NMR spectroscopy. Aggregate morphology was studied using cryo-TEM. The overall lipid uptake in the co-assembled aggregates was found to increase with the molar ratio of GM3 in the vesicles. The lipids present in the co-assembled aggregates have reduced acyl chain and headgroup dynamics compared to the protein-free bilayer system. These findings may improve our understanding of how different types of lipids can influence the composition of alpha Syn aggregates, which may have consequences for amyloid formation in vivo.

Automated summary

Parkinson's disease is characterized by the aggregation of the presynaptic protein alpha-synuclein (alpha Syn) and its co-assembly with lipids and other cellular matter in the brain. This study investigated the co-assembly of alpha Syn with model membranes containing the glycolipid ganglioside GM3 and found that the overall uptake of lipids in the co-assembled aggregates increases with the molar ratio of GM3 in the vesicles. The lipids present in the co-assembled aggregates exhibit reduced molecular dynamics compared to the protein-free bilayer system, which may have implications for the formation of amyloid in vivo.