How do ethanolamine plasmalogens contribute to order and structure of neurological membranes?

West A, Zoni V, Teague WE, Leonard JAN, Vanni S, Gawrisch K, Tristram-Negle S, Sachs JN, and Klauda JB. (2020) How do ethanolamine plasmalogens contribute to order and structure of neurological membranes? The Journal of Physical Chemistry B, 124

Plasmalogens are a specific class of lipids containing a vinyl-ether bond at the sn-1 position and a fatty acid connected with an acyl bond at sn-2. The predominant head group on plasmalogens is ethanolamine, producing ethanolamine plasmalogens (PlsEtns), which make up ~20% of all phospholipids in humans. Plasmalogens are characterized by their ability to protect from oxidative stress through scavenging radical oxygen species. They also play a role in cholesterol transport, lipid raft architecture, proper functioning of neurons, and synaptic vesicular fusion. Because of the large number of roles that PlsEtn have in cells, it’s not surprising that a plasmalogen deficiency has been associated with diseases including Alzheimer’s disease, Zellweger Syndrome, rhizomelic chondrodysplasia punctata, Parkinson’s disease, and multiple sclerosis. West et al analyzed phospholipid membrane components using x-ray diffuse scattering (XDS), nuclear magnetic resonance (NMR), and molecular dynamics simulations to study bilayer mixtures of phosphotidylethanolamine (PtdEtn; referred to as 1-palmitoyl-2- oleoyl-sn-glycero-3-phosphoethanolamine and POPE in the article), phosphotidylcholine (PtdCho; referred to as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and POPC in the article), and ethanolamine plasmalogen (PlsEtn; referred to as 1-(1Z-octadecenyl)-2-oleoyl-sn-glycero-3-phosphoethanolamine and PLAPE in the article).

To determine structural properties, including thickness, of the three mixed bilayers, XDS and NMR were utilized. As PtdEtn was added to PtdCho, the bilayer thickened. A similar trend was seen when PlsEtn was added to PtdCho, although in this case there was a greater increase in thickening compared to the addition of PtdEtn. This would suggest that the addition of plasmalogens provided additional structure and support to the membrane.

Molecular dynamic simulations were used to show the forces between atoms and displayed the interactions in the area per lipid (SA/lip), calculated by dividing the simulation box area by the number of lipids in the leaflet. The difference in SA/lip of the three ratios of PtdCho and PlsEtn (2:1, 1:1, and 1:2) at two temperatures was analyzed. From the three mixtures, the greatest SA/lip was found when the PtdCho and PlsEtn ratio was 2:1, with small decreases seen as the PlsEtn components increased. West et al suggest that this is due to the phosphoethanolamine headgroup forming hydrogen bonds to neighbouring lipids, causing a more closely aligned membrane. Since PlsEtns have a vinyl-ether bond, it is a larger lipid and less lipids can fit within the same sized leaflet. A pure PtdCho control was used as a base line and had the greatest SA/lip compared to the three mixtures. An increase in temperature also increases the SA/lip by 3-3.5 Å2.

It is established that plasmalogens have many roles in cellular functions and many of these stem from their importance in cellular membrane structure. West et al demonstrated how membrane plasmalogen concentration alters its structure. They found that increasing amounts of PlsEtn caused the membrane to thicken, also reducing the SA/lipid. It is important to note that neurological cell membranes are incredibly complex and contain many more constituents than were analyzed here, and that other components, such as cholesterol, will impact the SA/lipid value. The ratio of the different constituents is likely unique to the cell type and the characteristics its membrane requires, therefore there are likely physiological uses for all three ratios studied. Although it is described that PlsEtn reduced the number of lipids in a leaflet, West et al also explain that plasmalogens have the potential to protect proteins and DNA from oxidation. With many more molecules involved in membrane composition, further studies looking at the involvement of plasmalogens and the other components are necessary to fully understand their interactions and roles in the membrane.