Myelin lipids

Assuming that the overall stimulation is great enough, an electrical signal is fired down the length of the nerve (the axon). This axon is padded with sheaths of lipid (myelin sheaths) which act to insulate the signal as it passes down the axon. 

The use of labeled cholesterol or its precursor, mevalonate, has the appeal that a limited number of products are presumably formed and that the lipid is believed to turn over very slowly within the nervous system. It should be noted, however, that the observed slow cholesterol turnover reflects primarily the major brain pool of this lipid, myelin. Axonal flow studies are however directed at neurons, not at the glial cells that synthesize myelin. MacGregor et al., (1973) noted that following injection of cholesterol into the lumbar region of the chick, aproximodistal gradient of cholesterol was found in the sciatic nerve. The rate was thought to be about that observed for protein. Both cholesterol and cholesterol ester were detected, but the relative proportions were variable. A slow and fast rate of axonal flow were... 

The nervous system is a lipid-rich environment. As noted earlier, many elongated axons in the CNS and PNS are insulated by concentric layers of myelin that facilitate conduction of electrical impulses, ause of the density of the lipids, myelinated axons can be more sensitive to lipophilic neurotoxicants. Moreover, axons in adult CNS have a very limited ability to regenerate after injury, at least partially because of myelin-associated inhibitory factors from oligodendrocytes and "glial scars" from reactive astrocytes. In contrast, axons in the PNS have a greater potential to regenerate and regrow after injury under a different environment provided by Schwann cells. 

There is a second family of small lipid-binding proteins, the P2 family, which include among others cellular retinol- and fatty acid-binding proteins as well as a protein, P2, from myelin in the peripheral nervous system. However, members of this second family have ten antiparallel p strands in their barrels compared with the eight strands found in the barrels of the RBP superfamily. Members of the P2 family show no amino acid sequence homology to members of the RBP superfamily. Nevertheless, their three-dimensional structures have similar architecture and topology, being up-and-down P barrels. 

Figure 41-1. Ratio of protein to lipid in different membranes. Proteins equal or exceed the quantity of lipid in nearly all membranes. The outstanding exception is myelin, an electrical insulator found on many nerve fibers.

Exposures of 10 weeks (5 days/week) to 2,500 mg/kg/day trichloroethylene in com oil by gavage resulted in altered myelin thickness in the rat mental nerve, a branch of the trigeminal nerve (Barret et al. 1991). Effects of similar exposures on the rat trigeminal nerve included decreased fiber diameter and altered fatty acid composition in total lipid extracts, indicative of demyelination (Barret et al. 1992). Stronger effects were seen with the trichloroethylene decomposition product dichloroacetylene. 

Figure 4.4 Saltatory conduction. Transmission of electrical impulses in a myelinated axon occurs by way of saltatory conduction. Composed primarily of lipid, the myelin sheath insulates the axon and prevents generation of membrane potentials. Membrane potentials occur only at gaps in the myelin sheath, referred to as the nodes of Ranvier. Therefore, transmission of the impulse, or generation of action potentials, occurs only at the nodes.

Lipids have critical roles in nervous system structure and function. Synaptic complexes and myelin are characterized by unique lipid compositions that contribute to the specialized properties of these nervous system structures. Multiple signaling pathways involving lipid intermediates regulate cell differentiation and synaptic transmission. 

O Brien, J. S. and Sampson, E. L. Lipid composition of the normal human brain gray matter, white matter, and myelin. /. Lipid Res. 6 537-544.1965. 

The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fractionation 56 Central nervous system myelin is enriched in certain lipids 56 Peripheral and central nervous system myelin lipids are qualitatively similar 58... 

Sorting and transport of lipids and proteins takes place during myelin assembly 68... 

Information concerning myelin structure is also available from electron microscope studies, which visualize myelin as a series of alternating dark and less dark lines (protein layers) separated by unstained zones (the lipid hydrocarbon chains) (Figs 4-4 to 4-7). There is asymmetry in the staining of the protein layers. The less dark, or intraperiod, line represents the closely apposed outer protein... 

Myelin in situ has a water content of about 40%. The dry mass of both CNS and PNS myelin is characterized by a high proportion of lipid (70-85%) and, consequently, a low proportion of protein (15-30%). By comparison, most biological membranes have a higher ratio of proteins to lipids. The currently accepted view of membrane structure is that of a lipid bilayer with integral membrane proteins embedded in the bilayer and other extrinsic proteins attached to one surface or the other by weaker linkages. Proteins and lipids are asymmetrically distributed in this bilayer, with only partial asymmetry of the lipids. The proposed molecular architecture of the layered membranes of compact myelin fits such a concept (Fig. 4-11). Models of compact myelin are based on data from electron microscopy, immunostaining, X-ray diffraction, surface probes studies, structural abnormalities in mutant mice, correlations between structure and composition in various species, and predictions of protein structure from sequencing information [4]. 

Central nervous system myelin is enriched in certain lipids. Table 4-1 lists the composition of bovine, rat, and human myelin compared to bovine and human white matter, human gray matter, and rat whole brain [1] (see Ch. 3). While there are no absolutely myelin-specific lipids, cerebroside (galactosyl ceramide) is the most typical of myelin. With the exception of early development,... 

The data in Table 4-1 indicate that myelin accounts for much of the total lipid of white matter, and that the lipid composition of gray matter is quite different from that of myelin. The composition of brain myelin from all mammalian species studied is very much the same. There are, however, some species differences for example, myelin of rat has less sphingomyelin than does that of bovine or human (Table 4-1). Although not shown in the table, there are also regional variations for example, myelin isolated from the spinal cord has a higher lipid-to-protein ratio than brain myelin from the same species. 

Peripheral and central nervous system myelin lipids are qualitatively similar. However, there are quantitative differences. PNS myelin has less cerebroside and sulfatide and considerably more sphingomyelin than CNS myelin. Of interest is the presence of the LM1 ganglioside, sialosyl-lactoneotetraosylceramide, as a characteristic component of myelin in the PNS of some species. These differences in lipid composition between CNS and PNS myelin are not, however, as dramatic as the differences in protein composition discussed below. 

The MBPs are extrinsic proteins localized exclusively at the cytoplasmic surface in the major dense line (Fig. 4-11), a conclusion based on their amino acid sequence, inaccessibility to surface probes and direct localization at the electron microscope level by immunocytochemistry. There is evidence to suggest that MBP forms dimers, and it is believed to be the principal protein stabilizing the major dense line of CNS myelin, possibly by interacting with negatively charged lipids. A severe hypomyelination and failure of compaction of the major dense line in MBP deficient shiverer mutants supports this hypothesis (Table 4-2). 

Myelin components exhibit great heterogeneity of metabolic turnover. One of the novel characteristics of myelin demonstrated in early biochemical studies was that its overall rate of metabolic turnover is substantially slower than that of other neural membranes [1]. A standard type of experiment was to evaluate lipid or protein turnover by injecting rat brains with a radioactive metabolic precursor and then follow loss of radioactivity from individual components as a function of time. Structural lipid components of myelin, notably cholesterol, cerebro-side and sulfatide, as well as proteins of compact myelin, are relatively stable, with half-lives of the order of many months. One complication in interpreting these studies is that the metabolic turnover of individual myelin components is multiphasic - consisting of an initial rapid loss of radioactivity followed by a much longer slower loss. 

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