An Introduction to Plasmalogens in Honor of RCDP Awareness Day 2023

Jové M, Mota-Martorell N, Obis E, Sol J, Martín-Garí M, Ferrer I, Portero-Otin M, and Pamplona R. (2023) Ether lipid-mediated antioxidant defense in Alzheimer’s disease. Antioxidants

Plasmalogens are a unique class of lipid that contain a vinyl-ether bond at the sn-1 position. This conformation gives these lipids roles in cell membrane structure, membrane trafficking, cell signaling, and provide them with antioxidant properties. Reductions in plasmalogens have been associated with diseases such as Alzheimer’s disease, Gaucher’s disease, multiple sclerosis, and Parkinson’s disease. When there is an inability for plasmalogen biosynthesis this results in a severe deficiency in plasmalogens and causes rhizomelic chondrodysplasia punctata (RCDP). RCDP is a rare genetic disorder characterized by short stature, punctate calcifications in cartilage, congenital contractures, congenital cataracts, developmental delay, seizures, cardiac abnormalities, chronic respiratory illness, and shortened lifespan. These systemic effects demonstrate the importance of maintaining plasmalogen levels in the body, especially throughout early development.

When a human brain is healthy, it contains the greatest concentration of lipids in the body with lipids constituting 50% of the dry matter in the brain. Specific classes of lipids, including plasmalogens, are necessary for the structural and functional needs for membrane composition and organization of neurons and glial cells, as well as cellular signaling and homeostasis of oxidative stress. In their review, Jové et al hypothesized that there are lipid-derived adaptive mechanisms that are used by the body to maintain homeostasis of oxidative stress within the brain and to help maintain the health of neural cells.

Plasmalogens have many roles in the cell including membrane structure, membrane trafficking, cell signaling, and as an antioxidant. Here we will cover the first three roles and we will discuss their antioxidant properties in neurons and the changes to the lipidome specifically associated with Alzheimer’s disease in a following blog. Plasmalogens are essential structural components of cell membranes and subcellular compartments. The double bond in plasmalogens causes a more compact conformation and a tighter organization of the lipids in the membranes and reduces membrane fluidity. Also, plasmalogens have properties that influence membrane geometry and because of this, plasmalogen-rich membranes are more likely to form non-lamellar, inverse hexagonal structures which encourages membrane trafficking. This is particularly important for neurotransmission and is supported through plasmalogens being a large component of the membrane of synapses and synaptic vesicles. As well as being necessary structurally for cell signaling, different species of plasmalogens and other ether lipids are also signaling mediators. The pathways these mediators are involved in are thought to be for different neuronal and glial cell processes including energy metabolism, myelination, neurotransmission, oxidative stress, pro- and anti-inflammatory responses, and cholesterol homeostasis.

Plasmalogens are a unique class of lipid that contain a vinyl-ether bond which causes them to have a more compact structure. This allows plasmalogens to have very important cellular and subcellular roles in membrane structure, membrane trafficking, and cell signaling. Since these roles are essential for healthy cellular environments, when people are unable to make them it can have severe consequences including diseases such as RCDP. As well, reduced plasmalogen levels are associated with a range of other diseases. Further understanding of the role of plasmalogens in cells and the mechanisms behind the effects when they are not present are necessary for better understanding of the diseases described above and for potential plasmalogen replacement therapies.