Myelin turnover

A genetic disease, the 18q-syndrome is a rare leukodystrophy presenting a genomic deletion that includes the MBP gene. Proton magnetic resonance data indicate demyelination or increased myelin turnover rather than dysmyelination (Hausleretal., 2005). 

Results of relaxometry indicate a dysmyelination , as originally described by Hommes and Matsuo (1987) in the hyperphenylalaninemic rat, namely that the decreased synthesis of sulfatides and other myelin compartments is associated with an increased myelin turnover, leading to disruption splaying of myelin lamellae associated with increased water content. 

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... 

Fig. 4-11). Interestingly, the larger amounts of P2 protein that are in myelin of some species correlate with increased widths of the major dense lines as determined by X-ray diffraction, and there appears to be substantially more P2 in large sheaths than small ones [4]. The large variation in the amount and distribution of the protein from species to species and sheath to sheath raises so far unanswered questions about its function. Its similarities to cytoplasmic proteins in other cells, whose functions appear to involve solubilization and transport of fatty acids and retinoids, suggest that it might function similarly in myelin assembly or turnover, but there is currently no direct experimental evidence to support this hypothesis. 

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. 

A few enzymes, such as the previously mentioned CNP, are believed to be fairly specific for myelin/oligodendro-cytes. There is much more in the CNS than in peripheral nerve, suggesting some function more specialized to the CNS. In addition, a unique pH 7.2 cholesterol ester hydrolase is also enriched in myelin. On the other hand, there are many enzymes that are not myelin-specific but appear to be intrinsic to myelin and not contaminants. These include cAMP-stimulated kinase, calcium/calmodulin-dependent kinase, protein kinase C, a neutral protease activity and phosphoprotein phosphatases. The protein kinase C and phosphatase activities are presumed to be responsible for the rapid turnover of MBP phosphate groups, and the PLP acylation enzyme activity is also intrinsic to myelin. 

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. 

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. 

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.)... 

The brain is one of the most cholesterol rich organs of the body and contains 25% of total body cholesterol [92]. While the body manages cholesterol metabolism primarily through the liver, the brain cholesterol compartment is essentially isolated from body cholesterol pools by the blood brain barrier (BBB). During early CNS development, the rate of cholesterol synthesis is quite high due to extensive myelination. As the brain matures, cholesterol synthesis and turnover slow dramatically with an estimated total turnover rate ranging from 4-6 months [93] in adult rat brain. The turnover rate is even slower in humans than in rodents (0.03% per day vs. 0.4% in rodent) [94]. 

Recent studies confirm the initial observations of a decade ago that the turnover of myelin in adults is extremely slow. Myelin as a whole can be considered relatively stable, but various components are metabolized at different rates. The turnover rates (as measured by metabolic half-lives) of phosphotidylcholine, phosphotidylethanolainine, and phosphotidylserine are at least one-half as fast in myelin as in microsomes. Other lipids most probably turn over more slowly. Most lipids have turnover times in myelin on the order of weeks or months. Proteins have similar turnover times. In summary, the original proposal that myelin has a long-term metabolic stability appears accurate. However, various components turn over at different rates, and each component undergoes two phases, one of slow and one of fast degradation. Further information on the biochemistry, ultrastructure, and metabolism of myelin can be found in Bunge (1968), Davison and Peters (1970), Morell (1977), and Norton (1975). 

Small amounts of cholesterol can also be taken up into the nervous system from the blood following injection of C -cholesterol into 15-day-old rabbits. Once incorporated into the brain, C -cholesterol undergoes slow metabolism and is then retained with little apparent turnover for a period of at least 9 months. Spinal cord cholesterol is equally stable meta-bolically (Fig. 5). In the rabbit, as in the chicken, liver, kidney, and plasma cholesterol undergo quite rapid metabolism. In other experiments (Davison et al., 1959a) brains from rabbits, previously injected with 4-C -cholesterol, were separated into gray and white matter. It became apparent that all the turnover of the C -choIesterol was associated with the gray matter, and that there was little if any metabolism of cholesterol incorporated into the white matter. Since white matter is particularly rich in myelin, this suggested that once cholesterol has been incorporated into... 

It seems that a large proportion of adult rat, rabbit, or chicken brain cholesterol undergoes very slow metabolism. Since about 70% of brain cholesterol is located in the myelin sheath, it is probable that at least part of this structure is metabolically a relatively stable tissue component. Other studies on brain lipids support this view. Thus distribution of rat brain cerebroside sulfate is similar to that of cholesterol and turnover of sulfatide is also exceedingly slow. Furthermore, Davison and Gregson (1962) found that persisting radioactivity was associated primarily with the myelin fraction prepared from brains of rats previously injected with S -sulfate or methionine. 

Recent work with S - and P Mabeled substrates (Davison, 1964 Cuzner et al., 1965 Gregson and Davison, 1965) suggests that all the myelin sheath constituents—proteins and lipid— have the same turnover rate. However, a small part— possibly the outer lamellae—of the myelin sheath appears to be in a dynamic state and some of the labeled lipid can be taken up into a large slowly metabolizing pool. It therefore seems possible that membrane in intimate contact with cell cytoplasm is subject to catabolic and anabolic processes, but that much of the inner multi-lamellar structiure of myelin is physically inaccessible to such processes. 

Histochemical, cytochemical, developmental, and biochemical studies indicate that much of the brain cholesterol is localized in the lipid-protein layers of the myelin sheath. As a result, this cholesterol is largely removed from the normal metabolic environment of the brain. Thus, although nervous tissue contains relatively large amounts of lipid, biosynthesis and the mean turnover rate of the typical myelin lipids including cholesterol are quite slow. Nevertheless dynamic metabolism may be found in small pools of, for example, cell or organelle membrane, cytoplasmic lipid, or outer parts of the myelin sheath. Such possibilities may serve to explain some of the various anomalous results reported by many workers studying brain cholesterol metabolism. 

Little is known of the biosynthesis, breakdown, or role of sulfatides. Two observations seem established the biosynthesis of sulfatides coincides with the appearance of myelin and studies with the aid of a radioactive precursor have established a slow but definite turnover of sulfatides in the adult brain. Consequently, the brain constantly synthesizes and degrades sulfatides. Similar anabolic and catabolic processes are likely to occur in other tissues. 

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... 

Jungalwala (1974) has reported the presence of slow and fast turnover pools in myelin. Our own findings however indicate the presence of only a slowly turning over pool in this fraction. If the hypothesis advanced by Horrocks et al (1975) is true, one would not expect to find a rapid pool in myelin because the cytoplasmic side of the membrane would not be in contact with cytosol carrier proteins, except in young animals during myelination or in limited areas of adult iryelin This means that the slow turnover pool in myelin would represent the true half life of the membrane. 

---