Role of Lipid Composition on the Mechanical and Biochemical Vulnerability of Myelin and Its Implications for Demyelinating Disorders

The effect of hypothyroidism on the lipid composition of myelin and synaptosomes isolated from adult rat brain was investigated. The animals were made hypothyroid by adding 0.05% propyl-2-thiouracil to their drinking water for four weeks. This pathological state resulted in a significant increase in the relative percentage of choline glycerophospholipids in synaptosomes with a concomitant decrease in ethanolamine glycerophospholipids as compared to controls. In myelin, hypothyroidism significantly influenced only the relative percentage of sulfatides. The effect of the hypothyroid state on mature brain was also reflected in changes in the membrane fatty acid composition. Myelin and synaptosomes showed an increase in arachidonic (20:4) and eicosatrienoic (20:3) acids and an increase in the fatty acid unsaturation index. Furthermore, the 20:4/20:3 and 20:3/18:2 ratios were lower and higher, respectively, in treated animals. The data indicate that hypothyroidism affects the lipid composition of synaptosomes and myelin even though the effects were less pronounced in myelin. The lipid changes observed in hypothyroidism may be of physiological significance, as it is well known that lipid composition modulates various membrane-bound enzymes, transporters and receptors.

Compared with other mammalian tissues, retina is highly enriched in PUFA. Long-chain PUFA (LC-PUFA; C18-C24) are essential FAs that are enriched in the retina and are necessary for maintenance of normal retinal development and function. The retina, brain, and sperm also contain very LC-PUFA (VLC-PUFA; >C24). Although VLC-PUFA were discovered more than two decades ago, very little is known about their biosynthesis and functional roles in the retina. This is due mainly to intrinsic difficulties associated with working on these unusually long polyunsaturated hydrocarbon chains and their existence in small amounts. Recent studies on the FA elongase elongation of very long chain fatty acids-4 (ELOVL4) protein, however, suggest that VLC-PUFA probably play some uniquely important roles in the retina as well as the other tissues. Mutations in the ELOVL4 gene are found in patients with autosomal dominant Stargardt disease. Here, we review the recent literature on VLC-PUFA with special emphasis on the elongases responsible for their synthesis. We focus on a novel elongase, ELOVL4, involved in the synthesis of VLC-PUFA, and the importance of these FAs in maintaining the structural and functional integrity of retinal photoreceptors.

Enhancing Central Nervous System Remyelination in Multiple Sclerosis

When bacterial pathogens enter the gut, they encounter a complex milieu of signaling molecules and metabolites produced by host and microbial cells or derived from external sources such as the diet. This metabolomic landscape varies throughout the gut, thus establishing a biogeographical gradient of signals that may be sensed by pathogens and resident bacteria alike. Enteric bacterial pathogens have evolved elaborate mechanisms to appropriately regulate their virulence programs, which involves sensing and responding to many of these gut metabolites to facilitate successful gut colonization. Long chain fatty acids (LCFAs) represent major constituents of the gut metabolome that can impact bacterial functions. LCFAs serve as important nutrient sources for all cellular organisms and can function as signaling molecules that regulate bacterial metabolism, physiology, and behaviors. Moreover, in several enteric pathogens, including Salmonella enterica, Listeria monocytogenes, Vibrio cholerae, and enterohemorrhagic Escherichia coli, LCFA sensing results in the transcriptional repression of virulence through two general mechanisms. First, some LCFAs function as allosteric inhibitors that decrease the DNA binding affinities of transcriptional activators of virulence genes. Second, some LCFAs also modulate the activation of histidine kinase receptors, which alters downstream intracellular signaling networks to repress virulence. This mini-review will summarize recent studies that have investigated the molecular mechanisms by which different LCFA derivatives modulate the virulence of enteric pathogens, while also highlighting important gaps in the field regarding the roles of LCFAs as determinants of infection and disease.

Many degenerative diseases of the nervous system, including Multiple Sclerosis and peripheral neuropathies, are triggered by an impaired interaction between the axons and their surrounding myelin sheaths. The cause for this disturbed axon-myelin interaction, and the secondary neuronal damage that produces the clinical symptoms, lies in a primary defect of the myelin sheath. The myelin sheath itself is formed and maintained by oligodendrocytes and Schwann cells, the myelinating glial cells of the central and peripheral nervous system, respectively. The isoforms of the myelin-associated glycoprotein (MAG) are thought to be potential key elements of axon-myelin interaction, since these immunoglobulin-like cell signalling proteins are known to be localized in the periaxonal and paranodal myelin membranes. The MAG isoforms each display one of two possible intracellular C-termini as a result of alternative mRNA splicing. The C-terminus of the large isoform (L-MAG) has been shown to mediate downstream signals via the non-receptor tyrosine kinase Fyn, while the Cterminus of the short isoform (S-MAG) is thought to interact with the glial cytoskeleton. We have investigated the regulation and differential expression of L- and S-MAG in oligodendroglial cells and in transgenic mice by the use of genomic constructs that encode individually green fluorescent protein-tagged MAG isoforms. In the oligodendroglial cells LMAG was the dominant isoform prior to the stimulation of cells with cyclicAMP, whereas upon cyclicAMP stimulation, S-MAG was predominantly expressed in cells exhibiting advanced morphological differentiation. The investigation of our transgenic mice revealed that the two MAG isoforms are differentially expressed in distinct fibre tracts of the striatum and that S-MAG seems to be predominantly expressed in the long projecting fibres of the corpus callosum. Thus, the two MAG isoforms appear not only to be differentially expressed during development and in the adult, but they seem to mediate isoform-specific aspects of the axon-myelin interaction in distinct regions of the adult brain. A major question in the formation and maintenance of the myelin-axon interaction concerns the coordinated targeting of myelin signalling molecules and lipids to the different myelin compartments. Recent results suggest that glycolipid-enriched microdomains, socalled 'lipid-rafts', are involved in special sorting and trafficking mechanisms of membrane proteins and lipids. Furthermore, they are thought to serve as platforms for signal transduction processes. This makes them to interesting candidates for axon-myelin interactions, as well as for interactions between the apposed myelin membranes. The integral membrane protein 'Myelin and Lymphocyte Protein' (MAL) is suggested to be involved in lipid-raft-mediated protein targeting and signalling in myelinating cells. Our investigation of adult brain tissue of MAL-deficient mice showed that the incorporation of particular myelin components, such as MAG, into myelin membranes was significantly reduced. Thus, the targeting of L- and S-MAG to the myelin membranes appears to be dependent on the lipid-raft protein MAL. Furthermore, the MAL-deficient mice showed several ultra structural alterations comparable to those of the MAG-deficient mice and that reflect an impaired axon-myelin interaction. Our data supports the idea that-raft mediated trafficking of myelin constituents, such as MAG, to the different myelin compartments is a major task of adult oligodendrocytes in the context of maintaining the axonal contact of the myelin sheath. With the use of the isoform specific tagged MAG expressing mice, it will be possible for the first time, to investigate their differential function in axon-glia interaction as well as their dependence on MAL in vivo.

CNS-Resident Glial Progenitor/Stem Cells Produce Schwann Cells as well as Oligodendrocytes during Repair of CNS Demyelination

Long-chain fatty acids (LCFAs) are a tremendous source of metabolic energy, an essential component of membranes, and important effector molecules that regulate a myriad of cellular processes. As an energy-rich nutrient source, the role of LCFAs in promoting bacterial survival and infectivity is well appreciated. LCFA degradation generates a large number of reduced cofactors that may confer redox stress; therefore, it is imperative to understand how bacteria deal with this paradoxical situation. Although the LCFA utilization pathway has been studied in great detail, especially in Escherichia coli, where the earliest studies date back to the 1960s, the interconnection of LCFA degradation with bacterial stress responses remained largely unexplored. Recent work in E. coli shows that LCFA degradation induces oxidative stress and also impedes oxidative protein folding. Importantly, both issues arise due to the insufficiency of ubiquinone, a lipid-soluble electron carrier in the electron transport chain. However, to maintain redox homeostasis, bacteria induce sophisticated cellular responses. Here, we review these findings in light of our current knowledge of the LCFA metabolic pathway, metabolism-induced oxidative stress, the process of oxidative protein folding, and stress combat mechanisms. We discuss probable mechanisms for the activation of defense players during LCFA metabolism and the likely feedback imparted by them. We suggest that besides defending against intrinsic stresses, LCFA-mediated upregulation of stress response pathways primes bacteria to adapt to harsh external environments. Collectively, the interplay between LCFA metabolism and stress responses is likely an important factor that underlies the success of LCFA-utilizing bacteria in the host.

Robust In Vivo Transduction of Nervous System and Neural Stem Cells by Early Gestational Intra Amniotic Gene Transfer Using Lentiviral Vector

For fast propagation of action potentials in the nervous system, higher vertebrates have developed a specialized plasma membrane structure, the myelin, ensheathing nerve fibers. Myelin sheaths are formed by Schwann cells in the peripheral nervous system (PNS), whereas oligodendrocytes are the myelin-forming cells in the central nervous system (CNS). Impairment of the myelin sheath results in severe pathology as seen in multiple sclerosis in the CNS or polyneuropathies such as the Charcot-Marie-Tooth disease in the PNS. During development of peripheral nerves, a coordinated reciprocal signaling between Schwann cells and axons is crucial for accurate Schwann cell development, differentiation as well as maintenance of the myelin sheaths. In addition to orchestrated signal transduction, large amounts of lipids and membrane proteins are synthesized and have to be transported to distinct compartments for proper myelin formation. The transmembrane myelin and lymphocyte protein MAL is associated with lipid rafts, and is important for targeting proteins and lipids to distinct myelin membrane domains. In the PNS, MAL expression starts at around embryonic day 17, implicating a functional role in Schwann cell development. MAL overexpression retards the onset of peripheral myelination, and leads to reduced expression of p75NTR and myelin protein zero (P0). Since accurate expression of p75NTR is essential for proper initiation of myelination, it was suggested that altered p75NTR expression in MAL-overexpressing mice might be the cause of delayed onset of myelination. To elucidate a functional link between MAL overexpression and retarded myelination, primary mouse Schwann cell cultures were investigated. We could show that the induction of the CREB signaling pathway is functional, indicating that Schwann cells overexpressing MAL are not less responsive to axonal signals. Despite functional activation of the cAMP signaling pathway, significantly reduced mRNA expression levels of P0 and p75NTR were detected in untreated Schwann cells overexpressing MAL. This study revealed that most transcription factors known to modulate P0 expression were not altered in Schwann cells overexpressing MAL. During development, Schwann cells depend on accurate levels of different growth factors. To determine whether the delayed onset of myelination might be caused by a deficient downstream signaling of a particular growth factor, Schwann cells were treated with neuregulin1, nerve growth factor or fibroblast growth factor 1. However, none of the investigated growth factors could ameliorate the reduced expression of P0 and p75NTR in MAL-overexpressing Schwann cells. MAL-overexpressing Schwann cells were further investigated using a whole genome expression analysis. Most transcripts of genes implicated in Schwann cell development, differentiation and maintenance were not affected by MAL-overexpression. However, we identified a number of genes associated with cytoskeleton organization and components of the basal lamina that are regulated in a MAL-dependent manner. Especially during development and differentiation of Schwann cells, major changes in cellular processes and architecture are crucial for accurate radial sorting and myelination, proposing them as novel candidates for influencing myelination.

Intra-individual variability of long-chain fatty acids (C12–C24) in plasma and red blood cells

Do Myelin Oligodendrocyte Glycoprotein Antibodies Represent a Distinct Syndrome?

The present study examines the total lipid (TL) and fatty acid (FA) composition in eggs of brill Scophthalmus rhombus L. and the possible relationships with their quality parameters. Wild broodstocks were caught and maintained in captivity until eggs were collected. A lipid characterization of each egg batch was conducted in TL, lipid classes (LC) and FA of TL. The TL content was lower than the values reported for other flatfish species, showing high levels of sterol esters (SE). High viability rates were related to higher lipid reserves. Higher cholesterol (CHO) was linked to higher egg viability, whereas SE could have an opposite effect. Comparison of female quality showed that lipid composition was more related to egg batches than to individual females. However, multivariate analysis did not show a clear correlation between lipid composition and brill egg quality, neither as individual components nor as a whole profile of LC or FA. Our results suggest that some lipid components (phosphatidylcholine, CHO, SE, monounsaturated, eicosapentaenoic acid) could be related to differences in spawning quality, although these were not the only factors involved in these differences. Thus, these lipid components could be considered to be descriptors of the differences found in the rates of brill quality.

Myelin was isolated from subcortical areas of ten human brains, with ages ranging from 24 days to 350 days-of-age; samples were subsequently analyzed for lipid composition. Eight infants were victims of Sudden Infant Death Syndrome, and two infants were accident cases. Gray and white matter samples from each brain were also dissected and analyzed. Galactolipids were only 12% of the total lipids in white matter from brains of infants that were 24 days-of-age, a time when myelination was just starting in the subcortical areas. At 175 and 350 days of age, myelination was well underway and galactolipids measured 22% of the total lipids. Total phospholipids decreased (65% to 54%) in white matter during development, with the decrease mostly in phosphatidylcholine (23% to 15%). Even though there was little white matter present at early ages, myelin could be isolated. Surprisingly, the lipid composition of myelin from the 24-day-infant brain was similar to that from adult brain. Galactolipids were 22% of the total lipids, cholesterol, 23%, and phospholipids, 52%. These results suggest that only subtle remodeling of myelin occurs in humans once myelination commences. All four major gangliosides were present in myelin during this first year of development. Interestingly, the yield of myelin from the 350-day-old infant subcortical white matter was similar to that from an adult. Thus major tracts in this area may have acquired most of the myelin by one year-after-birth. Since the control samples blend quite well into the developmental pattern obtained, it is believed there are no abnormalities in myelin lipids from SIDS infants.

Long-chain fatty acids as nutrients for Gram-negative bacteria: stress, proliferation, and virulence.

Inflammatory demyelinating diseases such as multiple sclerosis (MS), neuro-myelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), acute inflammatory demyelinating polyradiculoneuropathy (AIDP), and chronic inflammatory demyelinating polyneuropathy (HIDP) are autoimmune diseases that affect the peripheral or central nervous system. In rare instances, demyelination may damage simultaneously the peripheral and central nervous system. Peripheral and central myelin have different protein components, but they also have some common ones such as myelin basic protein (MBP), myelin-associated glycoprotein (MAG), and neurofascin. Therefore, abnormal autoimmune responses against common antigens are suspected in the pathogenesis of demyelinating diseases with simultaneous central and peripheral nervous system involvement (1-3). In this paper, the case of a female patient was presented, whose neurologic finding showed the signs of peripheral and central nervous system damage existent at the same time, which was confirmed using electroneuromyography and magnetic resonance imaging of the brain. In terms of differential diagnosis, we took into consideration AIDP, HIDP, and other acquired demyelinating polyneuropathies that can occur concurrently with central nervous system demyelination and are very rare entities. In our female patient, the final diagnosis was made of a rare form of acute inflammatory demyelinating polyneuropathy with central nervous system demyelination. Establishing the final diagnosis was a key step in the management of the patient, since treatment protocols differed in the above demyelinating diseases. Further research should focus on autoantibodies targeting directly the common myelin epitopes in the Schwann cells of the peripheral nervous system and oligodendrocytes of the central nervous system (21).