Plasmalogens and the Peroxisome

A neuronal cell is shown on the left. The membrane surface of the cell is composed of the lipid membrane bilayer, which contains two rows of lipid molecules packed closely together. This layer essentially acts as a barrier, controlling what enters and leaves the cell. It also serves as the location for which many cell surface proteins, such as receptors, are anchored. Such cell surface proteins are involved in cell-cell communication, activation of signalling pathways involved in various cellular functions, and more.

There are multiple types of phospholipids that make up the cell membrane. Plasmalogens represent one class of lipids, as shown above, that contain the vinyl-ether bond (red box). In contrast, a conventional phospholipid contains two acyl bonds, as shown in the black box. In some cell types, such as neurons, over 50% of the cell membrane can be comprised of plasmalogens.

PLASMALOGEN PHOSPHOLIPIDS

The body is made up of millions of cells. Cells are discrete, structural units of living organisms that are separated from the extracellular environment by the lipid (also called plasma) membrane. This membrane is actually made up of two layers of lipids called phospholipids, which form what is called a lipid bilayer. There are multiple classes of phospholipids that pack together to form the lipid membrane bilayer. The membrane not only holds the contents of the cell together, but serves a number of other functions including nutrient transport, cell-cell communication, vesicular fusion, neurotransmission, and houses special microdomain regions required for the activity of various membrane-anchored protein receptors.   

Plasmalogens are a unique family of cell membrane glycerophospholipids that contain a vinyl-ether bond. A glycerophospholipid is built by the body through the attachment of fatty acids to a three-carbon glycerol backbone. Examples of fatty acids include those from the diet such as the 18-carbon linoleic and linolenic acids, DHA (a 22-carbon fatty acid), and many others. Fatty acids are joined to two carbons of the glycerol backbone (often referred to as the sn-1 and sn-2 positions) through specific chemical bonds. When the chemical bond connecting the fatty acid to the sn-1 position is a vinyl-ether bond, the lipid is referred to as a plasmalogen. 

PEROXISOMES

Within each cell there are a number of smaller organelles that serve various functions. The nucleus, for example, contains the DNA. The peroxisome is another tiny organelle that contains enzymes specifically involved in long-chain fatty acid metabolism, metabolism of catalase, and plasmalogen biosynthesis. 

There are two specific enzymes (proteins that carry out chemical reactions in the body) located in the peroxisome that make a critical ether-bond required for a plasmalogen. This ether bond is then converted to a vinyl-ether bond, which is the defining bond of a plasmalogen, by enzymes that are located outside of the peroxisome in another part of the cell called the endoplasmic reticulum (ER). As described above under GENETICS, all of the RCDP subtypes ultimately result from mutations in genes that in one way or another affect the peroxisome's ability to synthesize chemical reactions critical for the synthesis of plasmalogens.

KEY PLASMALOGEN FUNCTIONS

In-depth details of plasmalogen functions can be found in several excellent reviews on our Resources Page.  In the context of RCDP, precisely how reduced plasmalogen levels cause all of the symptoms of RCDP is still not clear, although there are a number of groups worldwide researching this. 

One of the main functions of plasmalogens is their effect on the physical structure of the cell membrane. Cell membranes containing plasmalogens have a different structure, being more highly-ordered and rigid. This is because the fatty acid side-chains are located more closely together due to the vinyl-ether bond, resulting in a more tightly-packed structure. One cell function, in particular, that is highly sensitive to the amount of plasmalogen in the membrane, is a process called vesicular fusion. Vesicular fusion occurs when small vesicles, located inside a cell, move contents to the outside of the cell by "fusing" its membrane with the cell membrane. The short video to the right really is worth a thousand words! 

The less plasmalogen in a cell membrane, the less likely it is that the vesicle will fuse to the cell membrane. One critical physiological function that is completely dependent on vesicular fusion is neurotransmission. Neurotransmission is the process whereby electrical signals, called action potentials, are relayed from the end of one neuron to the beginning of adjacent neurons. In simple terms, vesicles inside of neurons hold chemicals called neurotransmitters. When an action potential travels through a neuron and reaches the end-terminal, called the pre-synaptic terminal, it signals the vesicles containing neurotransmitters to fuse to the membrane, and in doing so, release their contents into the extracellular space (referred to as the synaptic cleft) between the ends of the neurons. The neurotransmitters then move through the presynaptic cleft and bind to receptors on the next neuron (called the post-synaptic terminal), resulting in the creation of a new action potential that propagates along the length of the neuron, and the process repeats. This process is also much easier to grasp through visualization as shown in the Chemical Synapse Animation above. 

Obviously, many physiological processes, both in the central and peripheral nervous systems, including muscle contractions, pain and discomfort, awareness, cognition, vision, and many others, rely on vesicular fusion-mediated neurotransmitter release. If membranes don't contain healthy amounts of plasmalogens, some of these functions will undoubtedly be compromised. 

An added complexity with RCDP is that because it is an inborn genetic condition, plasmalogens are deficient during embryonic and fetal development. How a plasmalogen deficiency leads to the developmental issues associated with RCDP is poorly understood. Certain aspects of the disease, such as the skeletal abnormalities, will likely not be reversible by any treatment, however, other aspects such as growth, discomfort, overall health, attention and awareness, quality of life, and lifespan, might be. The correlation between the severity of the disease and plasmalogen level provides hope that by augmenting plasmalogens therapeutically, improvement in at least some of these endpoints can be achievable. 

There are several other roles that plasmalogens play in the body. These include protection against oxidative stress, regulation of cholesterol levels, and formation of optimal cell membrane microdomains, which is another membrane structural phenomenon that is required for the function of many membrane-anchored proteins. More information on these functions can be found in the papers included on the Resources page. In addition we will expand in more detail on some of these functions in future posts.