Mielin

Myelin is a unique formation, the organization of which allows an electrical impulse to be conducted along a nerve fiber with minimal energy expenditure. The myelin sheath is a highly organized multilayer structure consisting of highly stretched and modified plasma membranes of Schwann (in the PNS) and oligodendroglial (in the CNS) cells.

The water content of myelin is about 40%. A distinctive feature of myelin compared to other cells is that it contains on average 70% lipids and 30% protein (based on dry weight). Most biological membranes have a higher protein to lipid ratio.

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CNS myelin lipids

All lipids found in rat brain are also present in myelin, i.e. there are no lipids localized exclusively in non-myelinated structures (except for the specific mitochondrial lipid diphosphatidylglycerol). The opposite is also true - there are no myelin lipids that are not found in other subcellular fractions of the brain.

Cerebroside is the most common component of myelin. Except in the earliest stages of development, the concentration of cerebroside in the brain is directly proportional to the amount of myelin in it. Only 1/5 of the total galactolipid content of myelin occurs in the sulfated form. Cerebrosides and sulfatides play an important role in ensuring the stability of myelin.

Myelin is also characterized by high levels of its main lipids - cholesterol, total galactolipids, and ethanolamine-containing plasmalogen. It has been established that up to 70% of the brain's cholesterol is found in myelin. Since almost half of the brain's white matter may consist of myelin, it is obvious that the brain contains the greatest amount of cholesterol compared to other organs. The high concentration of cholesterol in the brain, especially in myelin, is determined by the main function of neuronal tissue - to generate and conduct nerve impulses. The high cholesterol content in myelin and the uniqueness of its structure lead to a decrease in ion leakage through the neuron membrane (due to its high resistance).

Phosphatidylcholine is also an essential component of myelin, although sphingomyelin is present in relatively minor amounts.

The lipid composition of both gray matter and white matter in the brain differs markedly from that of myelin. The composition of brain myelin in all mammalian species studied is nearly identical; there are only minor differences (e.g., rat myelin has less sphingomyelin than bovine or human myelin). There are also some variations depending on the location of the myelin; for example, myelin isolated from the spinal cord has a higher lipid-to-protein ratio than myelin from the brain.

Myelin also contains polyphosphatidylinositols, of which triphosphoinositide accounts for 4 to 6% of the total phosphorus in myelin and diphosphoinositide for 1 to 1.5%. Minor components of myelin include at least three cerebroside esters and two glycerol-based lipids; some long-chain alkanes are also present. Mammalian myelin contains 0.1 to 0.3% gangliosides. Myelin contains more monosialoganglioside BM1 than is found in brain membranes. Myelin from many organisms, including humans, contains a unique ganglioside, sialosylgalactosylceramide OM4.

Myelin lipids of the PNS

Lipids of myelin of the peripheral and central nervous systems are qualitatively similar, but there are quantitative differences between them. Myelin of the PNS contains less cerebrosides and sulfatides and significantly more sphingomyelin than myelin of the CNS. It is interesting to note the presence of ganglioside OMR, which is characteristic of myelin of the PNS of some organisms. Differences in the lipid composition of myelin of the central and peripheral nervous systems are not as significant as their differences in protein composition.

CNS myelin proteins

The protein composition of CNS myelin is simpler than that of other brain membranes and is represented mainly by proteolipids and basic proteins, which make up 60-80% of the total. Glycoproteins are present in much smaller quantities. Myelin of the central nervous system contains unique proteins.

The myelin of the human CNS is characterized by the quantitative prevalence of two proteins: the positively charged cationic myelin protein (myelin basic protein, MBP) and the myelin proteolipid protein (myelin proteolipid protein, PLP). These proteins are the main components of the myelin of the CNS of all mammals.

Myelin proteolipid PLP (proteolipid protein), also known as Folch protein, has the ability to dissolve in organic solvents. The molecular weight of PLP is approximately 30 kDa (Da - dalton). Its amino acid sequence is extremely conservative, the molecule forms several domains. The PLP molecule includes three fatty acids, usually palmitic, oleic and stearic, connected to amino acid radicals by an ester bond.

CNS myelin contains slightly smaller amounts of another proteolipid, DM-20, named for its molecular weight (20 kDa). Both DNA analysis and primary structure elucidation have shown that DM-20 is formed by the cleavage of 35 amino acid residues from the PLP protein. DM-20 appears earlier in development than PLP (in some cases even before myelin appears); in addition to its structural role in myelin formation, it is thought to participate in oligodendrocyte differentiation.

Contrary to the idea that PLP is necessary for the formation of compact multilamellar myelin, myelin formation in PLP/DM-20 knockout mice occurs with only minor deviations. However, these mice have a reduced lifespan and impaired general mobility. In contrast, naturally occurring mutations in PLP, including its increased expression (normal PLP over-expression), have serious functional consequences. It should be noted that significant amounts of PLP and DM-20 proteins are present in the CNS, the messenger RNA for PLP is also present in the PNS, and a small amount of the protein is synthesized there but is not incorporated into myelin.

Myelin cationic protein (MCP) has attracted the attention of researchers due to its antigenic nature - when administered to animals, it causes an autoimmune reaction, the so-called experimental allergic encephalomyelitis, which is a model of a severe neurodegenerative disease - multiple sclerosis.

The amino acid sequence of MBP is highly conserved in many organisms. MBP is located on the cytoplasmic side of myelin membranes. It has a molecular weight of 18.5 kDa and lacks any signs of tertiary structure. This major protein exhibits microheterogeneity during electrophoresis under alkaline conditions. Most of the mammals studied contained different amounts of MBP isoforms that have a significant common part of the amino acid sequence. The molecular weight of MBP in mice and rats is 14 kDa. Low-molecular-weight MBP has the same amino acid sequences at the N- and C-terminal parts of the molecule as the rest of MBP, but differs in the reduction of about 40 amino acid residues. The ratio of these major proteins changes during development: mature rats and mice have more MBP with a molecular weight of 14 kDa than MBP with a molecular weight of 18 kDa. Two other isoforms of MBP, also found in many organisms, have molecular masses of 21.5 and 17 kDa, respectively. They are formed by the addition of a polypeptide sequence of about 3 kDa to the main structure.

Electrophoretic separation of myelin proteins reveals proteins with higher molecular weight. Their amount depends on the type of organism. For example, mice and rats can contain up to 30% of such proteins from the total amount. The content of these proteins also changes depending on the age of the animal: the younger it is, the less myelin in its brain, but the more proteins with higher molecular weight it contains.

The enzyme 2' 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) accounts for several percent of the total myelin protein content in CNS cells. This is much more than in other cell types. CNP protein is not the main component of compact myelin; it is concentrated only in certain areas of the myelin sheath associated with the oligodendrocyte cytoplasm. The protein is localized in the cytoplasm, but part of it is associated with the membrane cytoskeleton - F-actin and tubulin. The biological function of CNP may be to regulate the cytoskeleton structure to accelerate growth and differentiation processes in oligodendrocytes.

Myelin-associated glycoprotein (MAG) is a minor component of purified myelin, has a molecular weight of 100 kDa, and is present in the CNS in small quantities (less than 1% of the total protein). MAG has a single transmembrane domain that separates the highly glycosylated extracellular portion of the molecule, composed of five immunoglobulin-like domains, from the intracellular domain. Its overall structure is similar to neuronal cell adhesion protein (NCAM).

MAG is not present in compact, multilamellar myelin, but is located in the periaxonal membranes of oligodendrocytes that form myelin layers. Recall that the periaxonal membrane of the oligodendrocyte is the closest to the plasma membrane of the axon, but nevertheless these two membranes do not merge, but are separated by an extracellular gap. This feature of MAG localization, as well as the fact that this protein belongs to the immunoglobulin superfamily, confirms its participation in the processes of adhesion and information transfer (signaling) between the axolemma and myelin-forming oligodendrocytes during myelination. In addition, MAG is one of the components of the white matter of the central nervous system, which inhibits neurite growth in tissue culture.

Of the other glycoproteins of white matter and myelin, the minor myelin-oligodendrocytic glycoprotein (MOG) should be noted. MOG is a transmembrane protein containing a single immunoglobulin-like domain. Unlike MAG, which is located in the inner layers of myelin, MOG is localized in its surface layers, due to which it can participate in the transmission of extracellular information to the oligodendrocyte.

Minor amounts of characteristic membrane proteins can be identified by polyacrylamide gel electrophoresis (e.g. tubulin). High-resolution electrophoresis reveals the presence of other minor protein bands; these may be due to the presence of a number of myelin sheath enzymes.

Myelin proteins of the PNS

PNS myelin contains some unique proteins as well as some proteins in common with CNS myelin proteins.

P0 is the major protein of PNS myelin, has a molecular weight of 30 kDa, and accounts for more than half of the PNS myelin proteins. It is interesting to note that although it differs from PLP in amino acid sequence, post-translational modification pathways, and structure, both proteins are equally important for the formation of the structure of CNS and PNS myelin.

The content of MBP in the myelin of the PNS is 5-18% of the total protein, in contrast to the CNS, where its share reaches a third of the total protein. The same four forms of the MBP protein with molecular weights of 21, 18.5, 17 and 14 kDa, respectively, found in the myelin of the CNS, are also present in the PNS. In adult rodents, MBP with a molecular weight of 14 kDa (according to the classification of peripheral myelin proteins, it is named "Pr") is the most significant component of all cationic proteins. In the myelin of the PNS, MBP with a molecular weight of 18 kDa is also present (in this case, it is called "protein P1"). It should be noted that the importance of the MBP protein family is not as great for the myelin structure of the PNS as for the CNS.

PNS myelin glycoproteins

Compact myelin of the PNS contains a 22-kDa glycoprotein called peripheral myelin protein 22 (PMP-22), which accounts for less than 5% of the total protein content. PMP-22 has four transmembrane domains and one glycosylated domain. This protein does not play a significant structural role. However, abnormalities in the pmp-22 gene are responsible for some inherited human neuropathologies.

Several decades ago, it was believed that myelin formed an inert sheath that did not perform any biochemical functions. However, later, a large number of enzymes involved in the synthesis and metabolism of myelin components were discovered in myelin. A number of enzymes present in myelin are involved in the metabolism of phosphoinositides: phosphatidylinositol kinase, diphosphatidylinositol kinase, the corresponding phosphatases and diglyceride kinases. These enzymes are of interest due to the high concentration of polyphosphoinositides in myelin and their rapid metabolism. There is evidence of the presence of muscarinic cholinergic receptors, G proteins, phospholipases C and E, and protein kinase C in myelin.

Na/K-ATPase, which transports monovalent cations, and 6'-nucleotidase have been found in the myelin of the PNS. The presence of these enzymes suggests that myelin may be actively involved in axonal transport.