Although known for almost 80 years, the physiological role of plasmalogens (PLs), the major mammalian ether lipids (ELs), is still enigmatic. Humans that lack ELs suffer from rhizomelic chondrodysplasia punctata (RCDP), a peroxisomal disorder usually resulting in death in early childhood. In order to learn more about the functions of ELs, we generated a mouse model for RCDP by a targeted disruption of the dihydroxyacetonephosphate acyltransferase gene. The mutant mice revealed multiple abnormalities, such as male infertility, defects in eye development, cataract and optic nerve hypoplasia, some of which were also observed in RCDP. Mass spectroscopic analysis demonstrated the presence of highly unsaturated fatty acids including docosahexaenoic acid (DHA) in brain PLs and the occurrence of PLs in lipid raft microdomains (LRMs) isolated from brain myelin. In mutants, PLs were completely absent and the concentration of brain DHA was reduced. The marker proteins flotillin-1 and F3/contactin were found in brain LRMs in reduced concentrations. In addition, the gap junctional protein connexin 43, known to be recruited to LRMs and essential for lens development and spermatogenesis, was down-regulated in embryonic fibroblasts of the EL-deficient mice. Free cholesterol, an important constituent of LRMs, was found in these fibroblasts to be accumulated in a perinuclear compartment. These data suggest that the EL-deficient mice allow the identification of new phenotypes not related so far to EL-deficiency (male sterility, defects in myelination and optic nerve hypoplasia) and indicate that PLs are required for the correct assembly and function of LRMs.

The first steps of ether lipid biosynthesis are exclusively localized to peroxisomes and hence some peroxisomal disorders are characterized by a severe deficiency of plasmalogens, the main ether lipids in humans. Here we report on gene defects of plasmalogen biosynthesis, chromosomal localization of the corresponding genes and, as a consequence of plasmalogen deficiency, on structural alterations of caveolae, clathrin-coated pits, endoplasmic reticulum and Golgi cisternae, as well as on the reduced rate of transferrin receptor cycling. The data suggest that plasmalogens, analogous to cholesterol, are essential for correct membrane functioning and their deficiency results in impaired membrane trafficking.

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Clinical studies demonstrated favorable effects of statins in stroke beyond lipid-lowering effects. In acute stroke, the disruption of the blood-brain barrier (BBB) is mediated by matrix metalloproteinases (MMPs). A modified MMP metabolism may account for the beneficial effects of statins. Cultured human brain microvascular endothelial cells (BMECs) were pretreated with simvastatin and subjected to oxygen glucose deprivation (OGD). Gene expression and protein secretion of MMP-2 and MMP-9 and the tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 were measured by quantitative real-time polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Simvastatin significantly dampened the expression but not secretion of MMP-2 under OGD. MMP-9 synthesis rate was low and unaffected by simvastatin treatment, while the gene expression and protein secretion of TIMP-1 and TIMP-2 were both strongly induced. Our results provide evidence for a positive effect of simvastatin on the MMP metabolism in human BMECs and experimental stroke mainly by means of the increased expression and secretion of TIMP-1 and TIMP-2.