Myelin associated lipids

Myelin is modified plasma membrane. Myelin of the PNS resembles that of the CNS with respect to lipid composition. There is an enrichment in such specialized lipids as cerebroside and ethanolamine plasmalogen, and the high content of cholesterol plays an important role in control of membrane fluidity. The protein composition of PNS myelin is, however, distinct from that of CNS myelin. A single protein, P0, accounts for half of all protein of PNS myelin. Of the other proteins present, most are expressed in the CNS as well as the PNS but in quantitatively different amounts. Prominent among these proteins are myelin basic proteins and myelin-associated glycoprotein. 

Bichenkov, E and Ellingson, JS (1999) Temporal and quantitative expression of the myelin-associated lipids, ethanolamine plasmalogen, galactocerebroside, and sulfatide, in the differentiating CG-4 glial ceU line. Neurochem Res, 24, 1549-1556. 

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. 

Other leukodystrophies are associated with the lysosomal and peroxisomal disorders in which specific lipids or other substances accumulate due to a deficiency in a catabolic enzyme - for example Krabbe s disease, meta-chromatic leukodystrophy (MLD) and adrenoleuko-dystrophy (ALD) [1,2]. (These are discussed in detail in Ch. 40.) Similarly, disorders of amino acid metabolism can lead to hypomyelination - for example phenylketonuria and Canavan s disease (spongy degeneration) [1, 2, 25] (Ch. 40). The composition of myelin in the genetically... 

The function of the ALD protein is not fully understood, and knockout mice lacking it do not exhibit the severe CNS neurological deficits commonly associated with the human disease despite a similar accumulation of VLCFAs [26], Furthermore, the clinical variability in human patients cannot be accounted for by the severity of the biochemical abnormality or the nature of the gene defect. These observations, plus other data from mice with defects in VLCFA metabolism, raise the issue of whether the accumulation of VLCFAs in myelin is crucial to the pathological mechanisms or is an epiphenomenon. Unlike most other lipid-storage diseases, active ALD brain lesions are characterized by perivascular accumulation of lymphocytes. For this reason, it has been hypothesized that the severity of CNS pathology may relate to an autoimmune reaction that varies from patient to patient and... 

The cell membranes are predominantly a lipid matrix or can be considered a lipid barrier with an average width of a membrane being approximately 75 A. The membrane is described as the fluid mosaic model (Figure 6.2) which consist of (1) a bilayer of phospholipids with hydrocarbons oriented inward (hydrophobic phase), (2) hydrophilic heads oriented outward (hydrophilic phase), and (3) associated intra- and extracellular proteins and transverse the membrane. The ratio of lipid to protein varies from 5 1 for the myelin membrane to 1 5 for the inner structure of the mitochondria. However, 100% of the myelin membrane surface is lipid bilayer, whereas the inner membrane of the mitochondria may have only 40% lipid bilayer surface. In this example the proportion of membrane surface that is lipid will clearly influence distribution of toxicants of varying lipophilicity. 

Myelin basic proteins (MBP). Basic proteins are abundant both in CNS and PNS myelin, where they are associated with negatively charged lipids. They are assumed to be involved in myelin compaction on the cytoplasmic side of the membrane bilayer. A spontaneous MBP mutant, the shiverer mouse, is devoid of the major dense line of myelin in the CNS (Dupouey et al., 1979). Another such mutant, the Long Evans Shaker (LES) rat, shows major changes in spinal cord white matter, with dispersed labeling of Kvl.l and Kvl.2 K+ channel subunits as well as of Caspr, a molecule normally confined to paranodes along LES rat spinal axons (Eftekharpour et al, 2005). 

Even though some plasma membranes, such as nerve myelin membranes, contain a high concentration of lipids that form gel phase bilayers, the presence of cholesterol keeps these membranes in a fluid phase. However, interaction with the rigid cholesterol ring affects hydrocarbon chains of lipids in the liquid crystal phase (L ) and leads to formation of a new phase, the liquid ordered (Lq) phase (27). The phase is well characterized by a variety of physical methods and does not exist in pure lipids or their mixtures. In the liquid ordered phase, the long axis rotation and lateral diffusion rates are similar to the La phase, but the acyl chains are predominantly in an all-trans conformation and, hence, the order parameters are similar to the Lp phase (see Table 1). Recently, the cholesterol-rich Lq phase has been strongly associated with microdomains in live cells—the so-called lipid rafts. ... 

Myelin is approximately 75% lipid and 25% protein. Carbohydrate residues are associated with both the lipid and the protein components of myelin. High proportions of cholesterol, phospholipid, and glycolipid are found in the lipid fractions. Phospholipids include ethanolamine phosphatides, phosphatidylserine, and phosphatidylinositol glycolipids include both neutral (cerebroside, sulfatide, galactosyldiglyceride) and polar (gangliosides, especially GMj and GMJ lipids. A classification and discussion of the metabolism of brain lipids is beyond the scope of this article readers are referred to Lajtha (1969), Davison (1968), Awasthi and Srivastava (1980), and Suzuki (1981). 

Because lipophilicity is critical and SARs are not, relatively simple explanations of anesthetic activity are still appealing. Thus considering the known fact that such compounds do enter cellular membranes means that they are very likely to become intimately associated with lipoidal components of the membrane matrix that, in addition to the genuine lipids (e.g., myelin membranes in the brain are ca. 80% lipid), will include the larger alkyl and aryl portions of the amino acids of the protein components of the membranes. This may in turn result in a partial closure of the ion channels, thereby inhibiting polarization-depolarization of the membrane. 

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