Myelin, concepts

Myelin in situ has a water content of about 40%. The dry mass of both CNS and PNS myelin is characterized by a high proportion of lipid (70-85%) and, consequently, a low proportion of protein (15-30%). By comparison, most biological membranes have a higher ratio of proteins to lipids. The currently accepted view of membrane structure is that of a lipid bilayer with integral membrane proteins embedded in the bilayer and other extrinsic proteins attached to one surface or the other by weaker linkages. Proteins and lipids are asymmetrically distributed in this bilayer, with only partial asymmetry of the lipids. The proposed molecular architecture of the layered membranes of compact myelin fits such a concept (Fig. 4-11). Models of compact myelin are based on data from electron microscopy, immunostaining, X-ray diffraction, surface probes studies, structural abnormalities in mutant mice, correlations between structure and composition in various species, and predictions of protein structure from sequencing information [4]. 

The concept of ion-dipole interaction between lecithin and cholesterol has been suggested by many workers for the packing of these lipids in myelin or in the cell membrane (18, 19, 52). This concept is not supported by the surface potential measurements of mixed monolayers of lecithin and cholesterol. In contrast to dicetyl phosphate-cholesterol... 

It is possible that quite different molecular architectures may occur in membranes from different sources. Current research may result in a much more dramatic revision or complete rejection of the bilayer model for some membranes, especially in such systems as mitochondria (30) and chloroplasts (2). However, it is also possible that structural differences are only variations on the basic theme of the bilayer, from myelin at one extreme to mitochondria or chloroplasts on the other. One must not readily reject the fundamentals of the Danielli concept, especially in view of the present inadequate knowledge of the properties of phospholipids in water. Clearly the molecular architecture of membranes is speculative, but most aspects of the problem are amenable to direct experimental test by the new physical techniques. A consistent model for biological membranes will emerge quickly. 

Stys PK. Anoxic and ischemic injury of myelinated axons in cns white matter From mechanistic concepts to therapeutics. J Cereb Blood Flow Metab. 1998 18 2-25... 

Figure 108.3 Timing of thyroid hormone action in the deveioping brain. The timing of thyroid hormone (TH) insufficiency produces different effects in humans (upper panei) and rodents (iower panei). A concept is emerging that TH exerts effects on different brain regions as deveiopment proceeds. TH insufficiency during fetai deveiopment exerts effects on corticai deveiopment, but postnatal hypothyroidism exerts effects on cerebeiiar deveiopment. RC3, rat cortex cioue 3 NSP-A, neuroendocrine-specific protein-A MBP, myeline basic protein iGL, internai granuie iayer. Reproduced with permission from Zoeiier and Revet (2004).

With such an extensive knowledge base, what is the present state of our understanding of the mechanisms of this disorder Not unexpectedly, initial studies, primarily in experimental animal models, focused on the known metabolic pathways which involve thiamine. Indeed, the classical studies of Peters in 1930 (Peters, 1969) showed lactate accumulation in the brainstem of thiamine deficient birds with normalization of this in vitro when thiamine was added to the tissue. This led to the concept of the biochemical lesion of the brain in thiamine deficiency. The enzymes which depend on thiamine are shown in Fig. 14.1. They are transketolase, pyruvate and a-ketoglutarate dehydrogenase. Transketolase is involved in the pentose phosphate pathway needed to form nucleic acids and membrane lipids, including myelin. The ketoacid dehydrogenases are key enzymes of the Krebs cycle needed for energy (ATP) synthesis and also to form acetylcholine via Acetyl CoA synthesis. Decrease in activity of this cycle would result in anaerobic metabolism and lead to lactate formation (i.e., tissue acidosis) (Fig. 14.1). 

Interface instabilities, known as myelins, are an example of exotic nonequilibrium behavior present during dissolution in a number of surfactant systems. Although much is known about equilibrium phase behavior much still remains to be understood about nonequilibrium processes present in surfactant dissolution. In this chapter nucleation and growth, self and collective diffusion processes and nonlinear dynamics and instabilities observed in various polymeric systems are reviewed. These processes play an important role in our understanding of myelin instabilities. Kinetic maps and the concept of the free energy landscape provide a useful approach to rationalize some of the more complex behavior sometimes observed. 

Figure 3, above, explains the origin of the local variations in extracellular dopamine concentrations exhibited in the results obtained with microdisk electrodes. When placed randomly into the tissue, a microdisk electrode sometimes finds itself very near to a site of active dopamine release (a hot spot ), while on other occasions will find itself in a location where dopamine release does not occur (a cold spot ). The concept of hot and cold spots is consistent with the known architecture of the striatal region of the brain, which contains numerous bundles of myelinated nerve fibers that do not contain dopamine terminals if the small electrode were to be implanted in such a bundle, then indeed very little dopamine release would be observed at that location. 

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