Lipids Cholesterol is a major component of myelin, together with phospholipids and glycolipids, in ratios ranging from 4:3:2 to 4:4:2. Myelin phospholipids are not unusual, but myelin lipids are rich in glycosphingolipids, in particular galactocerebrosides (GalC) and their sulphated derivatives, sulphatides, which are used immunohistochemically to identify myelinating oligodendrocytes. The functions of GalC have been studied in mice with an inactive gene for the enzyme that catalyzes the final step in the synthesis of GalC (UDP-galactose:ceramide galactosyl transferase (CGT)). These mice have no detectable levels of GalC or sulphatides, and display a pronounced tremor starting at about two weeks (the age after birth when active myelination is at its peak in rodents). The abnormalities of internodal myelin spacing and the complete absence of transverse bands at the paranodal axo-glial junctions indicate an essential role for galactolipids in axon-glial interactions. The role of sulphatides has been examined in mice that lack cerebroside sulphotransferase, which also have disrupted paranodes, as well as greater numbers of differentiated oligodendrocytes.
There are also several minor galactolipids, such as fatty esters of cerebroside, and a number of gangliosides, GM4 being one of the most abundant in CNS myelin (but only a minor component in PNS), together with LM1 and GM3, which account for the large majority in PNS myelin. Mice lacking complex gangliosides
Figure 8.7 Myelin Composition:
A. The myelin sheath comprises layer upon layer of cell membrane and its main constituents are therefore lipids (70 per cent); these give the myelin sheath its insulating properties. The apposed cytoplasmic and extracellular interfaces of the compacted myelin lamellae (see Figure 8.6) respectively form the major dense line and intraperiod line; their fusion relies on a number of myelin-specific proteins, which are the second major constituents (30 per cent) of the myelin sheath.
B. The compositions of CNS and PNS myelin are largely equivalent, but they differ in a number of specific proteins. In the CNS, the major proteins are MBP and PLP, which respectively fuse the cytoplasmic and extracellular faces of the myelin lamellae; the absence of MBP or PLP respectively results in disruption of the major dense line and intraperiod line of the CNS myelin sheath. PNS myelin also contains MBP and PLP, but their functions are not clear. The major protein in PNS myelin is P0, which makes up more than 50 per cent of PNS myelin and mediates fusion of the myelin lamellae; PMP22 and Cx32 are also essential for PNS myelin formation. MAG is found in both CNS and PNS myelin and is important for membranemembrane interactions, in particular between the myelin and axon at paranodes; MOG is specific to CNS myelin.
Abbreviations: Cx32, connexin 32; MAG, myelin associated glycoprotein; MBP, myelin basic protein; MOG, myelin oligodendrocyte glycoprotein; P0, protein zero; PLP, proteolipid protein; PMP22, peripheral myelin protein 22
develop both CNS and PNS pathologies characterized by demyelination and axonal degeneration.
Myelin proteins are mostly specific to myelin. The major ones are myelin basic protein ((MBP) and proteolipid protein (PLP, and its isoform DM20), which constitute about 80 per cent of CNS protein. In addition, there are a number of proteins that make up a small but significant fraction of myelin, including 2',3'-cyclic nucleotide-3'-phosphodiesterase (CNP, 4 per cent), myelin associated glycoprotein (MAG, <1 per cent), and myelin oligodendrocyte glycoprotein (MOG, <0.1 per cent). Other proteins include myelin/oligodendrocyte specific protein (MOSP), myelin-associated/oligodendrocyte basic protein (MOBP), oligodendrocyte-myelin glycoprotein (OMgp), Nogo, P2, transferrin, carbonic anhydrase, and members of the tetraspan-protein family, including oligodendrocyte specific protein (OSP/claudin-11), gap junction protein connexins (Cx32, Cx47), and tetraspan-2, together with a number of enzymes that are important for myelin formation and turnover.
MBP is a family of proteins with many isoforms. The main function of MBP appears to be in the fusion of the cytoplasmic interface of the myelin lamellae and formation of the major dense line - a large deletion of the MBP gene in shiverer mutant mice results in the loss of the major dense line. Multiple isoforms of MBP are differentially expressed within oligodendrocyte somata and myelin, indicating they have multiple functions.
PLP constitutes up to 50 per cent of CNS myelin proteins, with two isoforms, PLP and DM20. There are spontaneous mutations involving the PLP gene, e.g. the jimpy (jp) mouse, myelin deficient (md) rats, and the shaking pup, and transgenic knockout mice have been developed. These studies indicate that PLP is important for fusing the extracellular face of the myelin lamellae and forming the intraperiod line. The absence of PLP/DM20 also results in axonal degeneration. In addition, in jimpy mice there are a number of developmental abnormalities, including premature oligodendrocyte cell death.
CNP is specific to oligodendrocytes in the CNS and Schwann cells in the PNS, but the functions of this enzyme in myelin are unresolved. It is expressed early in oligodendrocyte development and is used as a marker for this lineage. There are two isoforms, CNP1 and CNP2. In oligodendrocytes, CNP is localized immuno-histochemically to the cell body and processes, rather than compacted myelin. The lack of substrates for this enzyme in myelin has led to the suggestion of alternative functions, such as interaction with the actin cytoskeleton and microtubules to regulate process outgrowth. However, in the Cnpl knockout mouse, the myelin sheaths appeared normal, although there was axonal degeneration.
MAG is only a minor component of myelin (<1 per cent in the CNS and 0.1 per cent in the PNS), but it is the major glycoprotein. It consists of two isoforms, S(small)- and L(large)-MAG, which are differentially expressed during development. L-MAG is the predominant form in early myelination, but declines during development, and S-MAG is the predominant form in the adult. In the CNS, MAG is confined to the periaxonal cytoplasmic ridges of the myelin sheath, contrasting with a broader distribution in the PNS. MAG function has been studied in MAG knockout mice, where its absence results in abnormal formation of the paranodal loops and periaxonal cytoplasmic ridge, indicating a role for MAG in axon-myelin interactions. MAG is a member of the immunoglobulin (Ig) gene superfamily with significant homology to neural cell adhesion molecule (NCAM). The extracellular domain of MAG possesses the L2/HNK-1 epitope and binds to specific gangliosides on the axon membrane, which participate in recognition and adhesion. The cytoplasmic domain of MAG has several phosphorylation sites, and interacts with several transduction pathways, including Fyn, which is essential for myelination, and S100$ protein, which regulates the cytoskeleton and signal transduction. Hence, MAG is likely to play a major role in signal transduction across the myelin membrane. MAG is also an inhibitor of axon growth, and binds to the same receptor as Nogo and OMgp, with important implications for regeneration in the CNS.
MOG is specific to oligodendrocytes, and is mostly located on the cell surface and outermost lamellae of compacted myelin in the CNS. MOG expression is developmentally regulated and is one of the last myelin proteins to be expressed, making it a marker for mature oligodendrocytes. The function of MOG is unclear, but it is a member of the IgCAM superfamily, and may have similar adhesive and intracellular functions as MAG and P0. CNS myelin does not have a basal lamina and so MOG may be important in adhesion and interactions between adjacent sheaths within axon fascicles. MOG is the main antigen responsible for demyelination in the animal model of demyelination, experimental autoimmune encephalomyelitis (EAE).
MOBP is a relatively newly described family of CNS-specific myelin proteins. There are several MOBP isoforms that are relatively abundant and second only to MBPs and PLPs. MOBPs are located in the major dense line, where they may play a similar role to MBP. There are a number of MOBP isoforms that are differentially expressed within oligodendrocyte somata and myelin, suggesting that like MBP they have multiple functions. MOBP knockout mice have not revealed any clear abnormalities in myelin. MOBP has been used to induce EAE in mice and lymphocytes from patients with MS have autoreactivity to MOBP.
P2 is mainly a PNS protein, but is found in human CNS myelin, particularly in the spinal cord.
OMgp is localized to paranodal areas. Expression appears at the time of myeli-nation and may be important in axon-myelin sheath interactions. OMgp is another component of myelin that inhibits neurite outgrowth by binding to the Nogo receptor. In rat spinal cord, OMgp has been shown to be localized to cells (most likely NG2-glia/synantocytes), whose processes converge to form a ring that completely encircles the nodes. In OMgp knockout mice, nodes were abnormally wide and collateral sprouting was observed, indicating OMgp prevents axonal sprouting.
Nogo-A is abundantly expressed in both neurones and in oligodendroglial cell bodies and their myelin sheaths. Its function in oligodendrocytes is unresolved, and it is of greatest interest as one of the major axon growth inhibiting proteins in myelin. It is possible that Nogo, with MAG and OMgp, my help restrict axonal growth in the mature CNS.
MOSP is localized to the extracellular face of myelin, and its function is unresolved. The developmental expression of MOSP at the onset of myelination and the interactions of MOSP with microtubules suggest it may play a role in myelin formation.
Transferrin (Tf) is an iron transport glycoprotein found throughout the body, but is localized to oligodendrocytes in the CNS and its developmental expression matches myelination. Oligodendrocytes contain the four proteins which are responsible for the regulation and management of iron: transferrin, transferrin receptor, ferritin and iron responsive protein. Iron is a cofactor for several enzymes, and is a basic requirement for oxidative metabolism. Oligodendrocytes contain the highest levels of iron of any cell type in the brain, which may reflect the high metabolic load of myelin production. Studies in transgenic mice overexpressing Tf in oligodendrocytes suggest that Tf stimulates oligodendrocyte differentiation and myelination.
Carbonic anhydrases (CA) catalyze the reversible hydration of CO2, and are critical for the H+ buffering power of the CO2/HCO3- buffer system. Oligoden-drocytes may play a significant role in maintaining extracellular and intracellular pH, which is important for ion channel and transmitter receptor function. This is likely to play a role in ion and water movement in the myelin sheath, possibly important in the extrusion of cytoplasm from compacted myelin.
OSP/claudin-11 is structurally similar to PMP22 found in PNS myelin (see below) and is the third most abundant protein in CNS myelin. Studies of the OSP-deficient mouse indicate it is a tight junction protein important for the formation of the parallel arrays of tight junctions within myelin sheaths. In addition, OSP/claudin-11 is important in membrane interactions with the extracellular matrix, modulating proliferation and migration of oligodendrocyte progenitors.
There is also evidence implicating OSP/claudin-11 as an autoantigen in the development of autoimmune demyelinating disease.
Connexins: Cx32 is expressed by oligodendrocytes but its function is unresolved. Although absence of Cx32 in knockout mice results in peripheral demyelination, CNS myelination is unaffected. Cx47 expression in the CNS is specific to oligodendrocytes, and is regulated in parallel with myelin genes and partially colocalized with Cx32. Mice lacking either Cx47 or Cx32 are viable, but those lacking both connexins display marked abnormalities in CNS myelin, characterized by thin or absent myelin sheaths, vacuolation, enlarged periaxonal collars, oligodendrocyte cell death, and axonal loss. These studies indicate that gap-junction communication is crucial for CNS myelination, most likely forming a conduit for the movement of ions and water between cytoplasmic (uncompacted) and compacted regions of the myelin sheath.
Tetraspan 2 is expressed by cells of the oligodendrocyte lineage and developmental expression indicates it is likely to play a role in signalling in oligodendro-cytes in the early stages of their terminal differentiation into myelin-forming glia and may also function in stabilizing the mature sheath.
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