100th Blog

Plasmalogens are a unique class of phospholipids that contain a vinyl-ether bond at the sn-1 position on the glycerol backbone. This bond causes plasmalogens to have a more compact conformation which gives them structural roles in cellular membranes and makes plasmalogens an important component for vesicular fusion. In addition, plasmalogens have antioxidant properties because the vinyl-ether bond can scavenge radical oxygen species. Although plasmalogens are not the most well-known class of lipids, research into their structure and function in cells has been ongoing for nearly 100 years. The abundance of plasmalogens is dependent on tissue type, and reductions are associated with many diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and Gaucher’s disease. When people have a mutation in one of the genes involved in plasmalogen biosynthesis it results in Rhizomelic chondrodysplasia punctata (RCDP), a severe form of dwarfism which is characterized by shortened proximal bones, punctate calcifications, cataracts, seizures, developmental delays, cardiac and gastrointestinal issues, and recurrent respiratory illness. Continuing to research the roles of plasmalogens and the mechanisms that result in their decline is crucial. This literature blog series has set out to feature the ever-growing field of plasmalogen research and demonstrate their vital roles in our cells and the effects of alterations to their levels.

With the goal of highlighting plasmalogen research, an obvious topic for the literature blog was RCDP. In recent years, more work has been done to demonstrate the range in clinical presentations that are seen across individuals with RCDP. The severity of disease is entirely based on the amount of residual plasmalogen levels, where the individuals with a classic phenotype have nearly, if not completely, undetectable levels and a severe form of the disease while the milder phenotype presents in individuals with “non-classic” have an intermediate level of plasmalogens. Researchers have been able to provide examples of case studies from RCDP patients globally and help elucidate more details about the disease presentation, whether from a rare type of RCDP or a milder case. In some of the case studies, new variants of the genes that can result in RCDP have been discovered and further described. Early on in the life of the blog, the morbidity and mortality of RCDP was published which reported an increased 5 year survival probability of 75% in 2019 by Duker et al compared to the 60% probability reported in 2003 for these children. Gaining more awareness and information about this disease including updated growth charts, the prevalence of cardiac complications, or seizure frequency is fundamental for the development of a therapeutic but also for the families of people with RCDP so they can educate themselves and their family doctors.

As well, we have been able to share the plethora of work that has come out looking at the relationship between plasmalogens and Alzheimer’s disease (AD), a neurodegenerative disease characterized by progressive cognitive decline and memory loss. An association between reduced plasmalogen levels in people with AD has been well-established but the mechanisms behind this are still uncertain. Using large longitudinal studies such as the Australian Imaging Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) which were formed to identify biomarkers for AD, a negative correlation was found between plasmalogen levels and the disease, further supporting the role of this class of lipid in the progression of AD. Others have investigated whether supplementation with plasmalogen precursors could provide therapeutic benefits in animals models of AD. For example, it was shown that eicosapentaenoic acid-enriched ethanolamine plasmalogens (EPA-pPE) was able to reduce beta-amyloid and phosphorylated tau, toxic proteins thought to be involved in AD pathology, by ~60% and oxidative stress was shown to decrease in these animals. Another group has demonstrated the relationship between apolipoprotein (APOE) status, the greatest risk factor for sporadic AD, and lipid species and showed that those with the protective allele, APOE ε2, have the greatest plasmalogen levels and those with the allele associated with greatest risk, APOE ε4, have the lowest levels. 

Reduced plasmalogens have also been displayed in a range of other diseases and pathologies, and this work has been expanded on in the last few years. Gaucher’s disease (GD) is caused by a deficiency in the glucocerebrosidase enzyme which results in the buildup of fat in macrophage lysosomes. Interestingly, GD is a risk factor for developing Parkinson’s disease (PD) and both GD and PD are associated with reductions in plasmalogen levels. In fact, this reduction is theorized to be what links the two diseases. Barth syndrome (BTHS) is a rare genetic disorder that is characterized by muscle weakness, mitochondrial dysfunction and an enlarged heart, but it was shown that when patients were supplemented with plasmalogen precursors the lymphoblasts derived from these patients exhibited normalized cell viability, mitochondrial biogenesis, and mitochondrial membrane potential. Plasmalogens have also been associated with diseases caused by inflammation, including ulcerative colitis and rheumatoid arthritis, or oxidative stress, such as liver steatosis. As plasmalogens have many roles in our cells and are abundant in the brain, it is unsurprising that changes to plasmalogen levels and other lipid levels are seen in disorders such as Schizophrenia where significant differences have been documented in many classes of lipid and may be the cause of the increased oxidative stress seen in these people. A timely relationship has also been observed between plasmalogen levels, SARS-CoV-2 infection, and the resultant illness. Specifically, Deng and Angelova discussed how viral infection causes the cell membrane structure to change in response and form a cubic membrane (CM) which has antioxidant roles and acts as a defense system. Plasmalogens were shown to influence the abundance of CM that develops when pretreating with plasmalogens. This pretreatment caused more CM to form in response to viral exposure, therefore if a person has reduced plasmalogen levels this could impact the cell’s response to infection. Pike et al also demonstrated that plasmalogen levels are reduced during SARS-CoV-2 infection, sepsis, and sepsis-associated acute respiratory distress syndrome (ARDS), which can occur when an infection triggers an uncontrolled immune response.

In addition to the research directly associated to specific diseases, there are many people also expanding our knowledge on the structure, function, and mechanisms of plasmalogens using cell culture and animal models, which can later inform our knowledge of the role of plasmalogens in disease. Plasmalogens are a component of the cell membranes, but they have an asymmetric distribution within the lipid bilayer, where the inner leaflet is enriched with plasmalogens. Through knocking down four different type-IV P-type adenosine triphosphatases (P4-ATPases) in cells, Honsho et al determined that ATP8B2, a specific P4-ATPase, is responsible for this translocation. They also determined that the ATP8B2 enzyme is involved in sensing the quantity of plasmalogens in the inner leaflet so that when it is low, fatty acyl-CoA reductase (FAR1) can be upregulated so more can be synthesized. Recently, a proposed relationship between plasmalogens and hearing impairment was also investigated by another group. Pex3 mice, mice that have a mutation in a gene that is involved in peroxisome biosynthesis and integrity, were used to study this association. Based on studies by Kochaj et al it was suggested that reductions in plasmalogens in the inner ear may be what causes hearing impairment in Zellweger’s syndrome and that a targeted treatment to increase the levels in the inner ear may be effective enough to restore hearing.

We have now reached the 100th blog post, which itself is a testament to the vast amount of knowledge that has been discovered and shared by numerous researchers in the plasmalogen field. Plasmalogens are not a particularly well-known lipid, however they are fundamental for cell and tissue health. Taking together the immense number of pathologies that are associated with reduced or deficient plasmalogens and the large variety of other functions that have been determined, the criticality of plasmalogens is indisputable. Further work into the mechanisms plasmalogens are involved in and any structural differences between tissues or disease states will help inform researchers of their ability to be used as a therapy. In addition, elucidating whether any of these effects are caused by specific plasmalogen species or the overall plasmalogen pool will also aid supplement and drug development. We are excited to learn about new discoveries that are to come in the plasmalogen field.