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

Abstract

Ganglioside lipids have been associated with several physiological processes, including cell signaling. They have also been associated with amyloid aggregation in Parkinson’s and Alzheimer’s disease. In biological systems, gangliosides are present in a mix with other lipid species, and the structure and properties of these mixtures strongly depend on the proportions of the different components. Here, we study self-assembly in model mixtures composed of ganglioside GM1 and a zwitterionic phospholipid, 1,2-Dioleoyl-sn-glycero-3-phosphocholine (DOPC). We characterize the structure and molecular dynamics using a range of complementary techniques, including cryo-TEM, polarization transfer solid state NMR, diffusion NMR, small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and calorimetry. The main findings are: (1) The lipid acyl chains are more rigid in mixtures containing both lipid species compared to systems that only contain one of the lipids. (2) The system containing DOPC with 10 mol % GM1 contains both vesicles and micelles. (3) At higher GM1 concentrations, the sample is more heterogenous and also contains small disc-like or rod-like structures. Such a co-existence of structures can have a strong impact on the overall properties of the lipid system, including transport, solubilization, and partitioning, which can be crucial to the understanding of the role of gangliosides in biological systems.

Transient Lipid-Protein Structures and Selective Ganglioside Uptake During α-Synuclein-Lipid Co-aggregation

“…As a control, samples of dispersed lipids alone at t = 0 were imaged ( Figure 1A ). This control sample contains both unilamellar vesicles and small micelles, consistent with previous reports ( Mojumbar et al, 2019 ). Additionally, the effect of mechanical insult on aggregate morphology was investigated, through the imaging of final stage samples produced under quiescent and stirring (200 rpm) conditions, respectively ( Supplementary Figure S3 ).…”

“…The “blurry” and rod-like objects may be distinct structures, but it is possible that they represent the same type of object seen from different angles, e.g., ganglioside-rich lipodiscs ( Figure 2E ). Such lipodiscs can be stabilized by the ganglioside lipids with large sugar headgroups, and/or by the associated α-syn ( Eichmann et al, 2016 ; Mojumbar et al, 2019 ). Lipodiscs have indeed been detected for the lipid model with large hydrophilic headgroups ( Sandström et al, 2008 ; Zetterberg et al, 2016 ), as well as, for α-syn mixed with anionic phospholipids ( Eichmann et al, 2016 ).…”

The Role of Lipid Environment in Ganglioside GM1-Induced Amyloid β Aggregation

“…Over 60 gangliosides have been characterized in tissues of vertebrates that differ in the position and number of sialic acid residues [ 125 ]. Gangliosides represent nearly 6% of the total lipid content in the brain [ 103 ], but, in the neuronal plasma membrane, their concentration can reach up to 15 mol [ 126 ]. Together with SM and cholesterol, gangliosides are the main components of membrane microdomains.…”

“…In dependence on the surface charge density on membranes, the Aβ peptides may attain different conformational states that have fundamental impact on the aggregation process of amyloidogenic proteins. Hence, the disease-related changes in ganglioside levels as well as its clustering may have a dramatic effect on Aβ-induced neurotoxicity and amyloid plaques formation [ 126 ].…”

Editorial for Special Issue “Gangliosides: Modes of Action and Cell Fates”

“…These compounds are very useful to analyze the behaviors of GSLs on the membrane and/or inside of cells, and also to observe the interaction of GSLs with other membrane molecules, lectins, and the cell itself. Mojumdar et al developed a new system for the analysis of self-assembly in the ganglioside-phospholipid system [ 16 ]. This system is very useful to analyze actual behaviors of GSLs present with many phospholipids on the cell membrane.…”