Neurotransmitter Alterations in Ether Lipid Deficiency

Ether phospholipids are a specialized class of lipids that are characterized by an O-alkyl bond at the sn-1 position of their glycerol backbone. The initial steps of their de novo biosynthesis take place in the peroxisome. Plasmalogens constitute the most prominent type of ether lipids in the mammalian body and are a structural component of cellular membranes, which makes them essential constituents of the mammalian body. They perform highly important physiological functions like scavenging of radicals and storage of polyunsaturated fatty acids. Therefore, the consequences of ether lipid deficiency are dramatic, causing the fatal human disease rhizomelic chondrodysplasia punctata (RCDP), which is evoked by genetic defects concerning the crucial peroxisomal biosynthetic enzymes. However, although their abundance and importance, in particular for the central nervous system, has been known for decades, the exact role of plasmalogens and the molecular consequences of their absence in the human body are largely unknown. A role for these compounds in neurotransmission, the process, in which a signal is relayed from one neuron to another by substances called neurotransmitters, has been proposed but never shown. Our preliminary results point towards several abnormalities concerning neurotransmitters in an ether lipid-deficient mouse model. Therefore, within this project, we will contribute to the understanding of the role of plasmalogens in the complex process of neurotransmission. By using a knockout mouse model, which is unable to synthesize ether lipids, as well as post mortem human brain tissue from RCDP patients, we will describe in detail the effects of the lack of ether lipids on neurotransmitters and neurotransmission. Furthermore, we aim to elucidate the molecular mechanism underlying such abnormalities. Next, we will examine the behavioral consequences of neurotransmitter alterations caused by ether lipid deficiency in the mouse model. Several groups have shown that dietary ether lipid supplements can normalize plasmalogen levels in the periphery, but not in the brain, which precludes relief of the most severe impairments provoked by ether lipid deficiency. We have formulated a new hypothesis that would explain the mechanism preventing the entry of ether lipid supplements into the brain. By means of a novel strategy we will aim to overcome this problem and contribute substantially to the development of a therapy for RCDP.

In this project, we investigated the role of ether lipids in the central nervous system, particularly in synaptic transmission, the process, by which neurons communicate with each other. Ether lipids, the most abundant of which are termed plasmalogens, constitute a subgroup of phospholipids. The molecular functions of these lipids are mostly unknown, although it has been shown that, due to their unique biophysical features, they shape properties and functions of biological membranes. Based on the knowledge that plasmalogens are highly abundant in synapses, we proposed that the deficiency to synthesize ether lipids, in humans evoking the fatal disease rhizomelic chondrodysplasia punctata (RCDP), would impair synaptic transmission in vivo. To test this hypothesis and identify the underlying molecular mechanisms as well as the physiological implications, we employed a mouse model of complete ether lipid deficiency.