Myelin metabolism

In Chapter in we drew attention to the fact that some nerve fibres are myelinated. It has been suggested that the pseudocholinesterase of the central nervous system may be concerned in myelin metabolism and that inhibition of pseudo-cholinesterase... 

Andreasen et al (1993) ... aspects of brain structure that reflect quality rather than quantity of brain tissue complexity of circuitry, dendritic expansion, number of synapses, thickness of myelin, metabolic efficiency, or efficiency of neurotransmitter production, release, and reuptake. Factors such as these would facilitate the speed and efficiency of information transfer within the brain as well as expand its capacity, so that multiple tasks of multiple kinds could be performed simultaneously. The greater volume of grey matter can be postulated to reflect a greater number of nerve cell bodies and dendritic expansion a greater number of neuronal connections presumably enhances the efficiency of computational processing in the brain. ... 

Impairment in cholesterol synthesis and disturbances in myelin metabolism [33]... 

Hommes FA. Amino addaemias and brain maturation interference with sulphate activation and myelin metabolism. J Inherit Metab Dis. 1985 8 Suppl 2 121-2. 

Steinfeld, R., Grapp, M., Kraetzner, R., Dreha-Kulaczewski, S., Helms, G., Dechert, P., Wevers, R., Grosso, S., and Gartner J., 2009. FDolate receptor alpha defect causes cerebral folate transport deficiency a treatable neuro-degenerative disorder associated with disturbed myelin metabolism. American Journal of Human Genetics. 85 354-363. 

The composition of myelin changes during development 68 Spontaneous mutations in experimental animals provide insights about the structure and assembly of myelin 68 Myelin components exhibit great heterogeneity of metabolic turnover 69... 

Enzymes associated with myelin. Several decades ago it was generally believed that myelin was an inert membrane that did not carry out any biochemical functions. More recently, however, a large number of enzymes have been discovered in myelin [37]. These findings imply that myelin is metabolically active in synthesis, processing and metabolic turnover of some of its own components. Additionally, it may play an active role in ion transport with respect not only to maintenance of its own structure but also to participation in ion buffering near the axon. 

Other enzymes present in myelin include those involved in phosphoinositide metabolism phosphatidylinositol kinase, diphosphoinositide kinase, the corresponding phosphatases and diglyceride kinases. These are of interest because of the high concentration of polyphosphoinositides of myelin and the rapid turnover of their phosphate groups. This area of research has expanded towards characterization of signal transduction system(s), with evidence of G proteins and phospholipases C and D in myelin. 

Certain enzymes shown to be present in myelin could be involved in ion transport. Carbonic anhydrase has generally been considered a soluble enzyme and a glial marker but myelin accounts for a large part of the membrane-bound form in brain. This enzyme may play a role in removal of carbonic acid from metabolically active axons. The enzymes 5 -nucleotidase and Na+, K+-ATPase have long been considered specific markers for plasma membranes and are found in myelin at low levels. The 5 -nucleotidase activity may be related to a transport mechanism for adenosine, and Na+, K+-ATPase could well be involved in transport of monovalent cations. The presence of these enzymes suggests that myelin may have an active role in ion transport in and out of the axon. In connection with this hypothesis, it is of interest that the PLP gene family may have evolved from a pore-forming polypeptide [9],... 

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. 

For example, initially MBP and PLP exhibit half-lives of 2-3 weeks, but later their half-lives are too long to be calculated accurately. A possible interpretation of these data is that some of the newly formed myelin remains in outer layers or near cytoplasmic pockets (incisures and lateral loops) where it is accessible for catabolism - thus accounting for the rapidly turning-over pool. The more stable metabolic pool would consist of deeper layers of myelin less accessible for metabolic turnover. 

The rate of blood flow in different structures of the brain reaches peak levels at different developmental stages, depending on the maturation rate of the particular structure. In structures that consist predominantly of white matter, the peaks coincide roughly with maximal rates of myelination. From these peaks, blood flow and, probably, cerebral metabolic rate decline to the levels characteristic of adulthood [2,39,44],... 

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

Familial demyelinative/dysmyelinative and axonal neuropathies may also be caused by impaired lysosomal lipid metabolism. Metachromatic leukodystrophy (sulfatide lipidosis) results from mutations of the arylsulfatase A gene, which encodes a lysosomal enzyme required for sulfatide turnover. Myelin is affected in both CNS and PNS, though dysfunction is restricted to the PNS in some patients, and the onset of symptoms can occur at any time between infancy and adulthood. Bone marrow transplantation can slow disease progression and improve nerve conduction velocities [57]. (See in Ch. 41.)... 

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... 

Imbalances of brain amino acids may hinder the synthesis of brain lipids, leading to a diminution in the rate of myelin formation. Decreases of lipids, proteolipids and cerebrosides (Ch. 3) have been noted in several of these syndromes, e.g. maple syrup urine disease, when intra-myelinic edema is a prominent finding, particularly during the acute phase of metabolic decompensation [9]. Pathological changes in brain myelin are common, especially in infants who die early in life. The fundamental... 

Oligodendrocytes are present in the CNS as well and wrap around axons to form a myelin sheath. Myelin wraps into concentric layers that spiral around the axon. Gaps in the oligodendrocytes are the nodes of Ranvier, where the membrane maintains contact with extracellular fluid. The nodes serve to propagate the action potential in myelinated axons. Schwann cells perform an analogous function, myelinating axons in the peripheral nervous system. Not all neurons are myelinated, but myelination increases the metabolic efficiency of action potentials. Demyelination of neurons produces deficits in neuronal conduction, as is seen in multiple sclerosis. 

Conduction of the action potential in myelinated axons is called saltatory conduction. Because ion flux only occurs at the nodes of Ranvier, the action potential jumps, in effect, from node to node. This provides two advantages, speeding the rate of conduction and reducing the metabolic cost of an action potential, because energy-dependent ion transporters are not needed along myelinated segments. 

The biochemical basis nnderlying the normal fnnctioning of the brain is discussed above, where it is emphasised that of the two forms of communication, electrical and chemical, it is the latter that provides most flexibility. Not snrprisingly, therefore, there are more disorders dne to disturbances in neurotransmitter metabolism than there are due to disturbances in electrical commnnication. Nonetheless, damage to the structure of the myelin sheath aronnd the axon which interferes with electrical commnnication can lead to the severe disorder mnltiple sclerosis. 

Bi (thiamine) Fresh vegetables, husk of cereal grains, meats, especially hver Energy metabolism, synthesis of myelin... 

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