Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment

Malheiro AR, Correia B, Ferreira da Silva T, Bessa-Neto D, Van Veldhoven PP, and Brites P. (2019) Leukodystrophy caused by plasmalogen deficiency rescued by glyceryl 1-myristyl ether treatment. Brain Pathology, 1-18.

Within the central nervous system (CNS), myelin acts an insulating layer along the axon of neurons and allows for more efficient transmission of signals between the cells. It is well documented that when myelin is disrupted, it results in a number of diseases, most notably multiple sclerosis (MS). However, loss of myelin is also associated with Alzheimer’s disease, a neurodegenerative disorder resulting in cognitive decline and memory loss, and rhizomelic chondrodysplasia punctata (RCDP), a severe form of dwarfism that is caused by the inability to produce plasmalogens. A recent study analyzed the effects of plasmalogen deficiency on myelination using the Gnpat genetic knockout (KO) mouse model, which is unable to synthesize plasmalogens due to a mutation in one of the initial enzymes in the biosynthesis pathway (glycerophosphate O-acyltransferase; GNPAT). Wild-type and Gnpat KO mice were characterized and used to produce a primary oligodendrocyte precursor (OPC) culture.

Using transmission electron microscopy, distinct demyelination was observed in the spinal cord, optic nerve, corpus callosum, internal capsule, and cerebellum of the Gnpat KO mice when compared to wild-type mice. Demyelination correlated with the development of a progressive neurological condition including tremors and general ataxia, which are similar to the symptoms that present in people with MS. In the Gnpat KO mice, these symptoms began at nine-months of age and worsened after one year of age, eventually causing limb paralysis. Although demyelination was observed at later ages, initially during the early postnatal period, normal densities of oligodendrocytes could be seen within the spinal cords and optic nerves of the Gnpat KO mice. Consequently, it appears that the importance of plasmalogens in the formation and maintenance of myelin differs across ages, suggesting that there may be age-specific mechanisms involved. This theory was further supported by the reported differential expression of other myelin markers when compared between the age groups. Oligodendrocyte precursor cells must migrate to their proper location, then differentiate before they can form myelin. No difference was seen in OPC or oligodendrocyte numbers in the early postnatal period, suggesting that plasmalogens are not critical for the proper OPC migration. However, the differentiated cells were disrupted in the formation and maintenance of myelin, indicating the importance of plasmalogens for myelination later in the postnatal period.

Interestingly, treatment of an in vitro model of cultured OPCs with glyceryl 1-myristyl ether (1-O-tetradecyl glycerol; 1-O-TDG), an ether plasmalogen precursor, recovered both the number of myelinated oligodendrocytes and the length of the myelinated segments. As myelin is known to contain high amounts of plasmalogens, making up around 70% of the ethanolamine glycerophospholipids within myelin, it is obvious why a deficiency could have such a significant effect. Taken together, Malheiro and coauthors demonstrated the importance of adequate plasmalogen levels for proper oligodendrocyte function and myelination, as well that the age-dependent role plasmalogens play in myelin formation. The findings are consistent with the hypothesis that plasmalogen augmentation might offer a potential strategy to rescue demyelination in patients with MS and RCDP.