Regulation of plasmalogen biosynthesis in mammalian cells and tissues.

Honsho M and Fujiki Y. (2023) Regulation of plasmalogen biosynthesis in mammalian cells and tissues. Brain Research Bulletin

Plasmalogens are a class of phospholipid with a vinyl-ether bond at sn-1 causing a more compact conformation. These lipids are important for cell membrane structure and fluidity, vesicular fusion, lipid raft formation, cholesterol transport, and make up a large proportion of the lipids in the mammalian brain. Since these lipids have such important roles in the body, a plasmalogen deficiency has systemic effects. Rhizomelic chondrodysplasia punctata (RCDP) is an ultra-rare disease and is characterized by proximal shortening of upper limbs, congenital cataracts, seizures, cardiac defects, and recurrent respiratory illness. RCDP is caused by an inability to produce plasmalogens from a mutation in one of five genes that encode enzymes in the plasmalogen biosynthetic pathway. Briefly, plasmalogen biosynthesis begins in the peroxisome with glyceronephosphate O-acyltransferase (GNPAT) which catalyzes the synthesis of acyl-dihydroxyacetone phosphate (acyl-DHAP). This is further metabolized to alkyl-DHAP by alkylglycerone phosphate synthase (AGPS) which replaces the fatty acids within acyl-DHAP with long-chain fatty alcohols. For this step to occur, peroxisomal biogenesis factor 7 (PEX7) needs to recognize the peroxisomal targeting tag, encoded by PEX5, on AGPS and transport it into the peroxisome. As well, fatty acyl-CoA reductase 1 (FAR1) is responsible for producing the fatty alcohols that get incorporated by AGPS. Later, plasmanylethanolamine desaturase (PEDS) introduces the vinyl-ether bond and is the final step in plasmalogen biosynthesis. The review article by Honsho and Fujiki focuses on the regulation of plasmalogen biosynthesis in cells and tissues and how this affects pathology.

To regulate plasmalogen biosynthesis an important concept is plasmalogen sensing, however the mechanism for this is unknown. It has been shown that plasmalogens are largely concentrated in the inner leaflet by P4-type-ATPases (discussed further in a previous blog) and altering the levels in the outer leaflet occurs through reducing the expression of CDC50A, the gene that encodes the β-subunit of P4-type-ATPases which is responsible for transferring these enzymes from the endoplasmic reticulum. In addition to sensing where plasmalogens are in the membrane and translocating them to another location, enzymes such as TMEM189, a plasmalogen desaturase, can degrade FAR1 which would also impact plasmalogen biosynthesis.

Although work has been done to analyze plasmalogen biosynthesis regulation in cells, this has not been looked at directly in tissues. The closest research has come is through administering a plasmalogen precursor, like alkylglycerol (AG), to plasmalogen deficient mice such as Pex7 knockout (KO) or Gnpat KO mice. Any change to plasmalogen levels in this instance could suggest how plasmalogen synthesis is regulated. In the case of AG, peripheral tissues showed increased levels however, the brain did not. Honsho and Fujiki suggest that this could indicate that there is a mechanism that senses plasmalogen levels in the peripheral tissues that regulates plasmalogen biosynthesis. Also that the bulk of plasmalogens in the brain may be produced by brain cells and not produced from periphery and taken up through the bloodstream.

Honsho and Fujiki were interested in reviewing the literature on the regulation of plasmalogen biosynthesis. The specific mechanisms involved in this regulation and the signalling pathways involved are largely unknown, but recent work has provided some answers. There are many enzymes involved in the synthetic pathway and it has been shown that dysfunction of these enzymes prevents the production of plasmalogens depending on the step that this occurs in. Administering exogenous plasmalogen precursors can help replenish plasmalogen levels, but most improvements have been detected in peripheral tissues with changes to brain levels being rare. The treatment would have to cross the blood-brain barrier before changes could be detected so this could be due to not treating for a long enough time or a lower concentration of treatment. As well, plasmalogens have an asymmetrical distribution on the membrane leaflets with the majority being on the inner leaflet. This distribution requires plasmalogen sensing and flippases to translocate plasmalogens. Some form of plasmalogen sensing is likely required to regulate plasmalogen biosynthesis as well through detecting plasmalogen levels and levels lysoplasmalogens, their metabolite. This regulation can also occur by degrading synthetic enzymes, such as FAR1, when plasmalogen levels get too high. Further work into the regulation and homeostasis of plasmalogens is necessary to fully elucidate these processes and for the development of molecules that can be used to raise plasmalogen levels when there is a deficiency.