Myelin Synthesis Research Articles

Sterol and fatty acid synthesis in developing brains of three myelin-deficient mouse mutants

1. 1. The rate of sterol synthesis and the level of hydroxymethylglutaryl-CoA (HMG-CoA) reductase were previously shown to be subnormal in the myelin-deficient brains of jimpy ( jp/Y) mutants. To determine whether these changes were specific for the jimpy mutation, rates of sterol synthesis and other aspects of lipid synthesis in jimpy brains were compared with those in the brains of two other mutants with defective myelination of the central nervous system, quaking ( qk/qk) and myelin synthesis deficiency ( msd/Y). 2. 2. The rate of sterol synthesis from [1- 14C]acetate or from [2- 14C]mevalonic acid and the level of HMG-CoA reductase were depressed in all three mutations at the earliest age at which clinical symptoms of the disorders were apparent. Ratios of cholesterol to desmosterol in developing brains of the three mutations were normal. 3. 3. The heat stability and the K m (HMG-CoA) of brain HMG-CoA reductase were not affected by the three mutations. 4. 4. The rate of fatty acid synthesis from [1- 14C]acetate was depressed in qk/qk brains but not in jp/Y or msd/Y brains. 5. 5. Rates of sterol, fatty acid, and CO 2 production in brain were not reduced in two neuromuscular mutants (reeler ( rl/rl) and oscillator ot/ot) with depressed growth rates but without known myelin deficiencies or in normal immature mice deprived of food, indicating that inadequate nutrition was not a cause for the observed deficiencies in lipid synthesis rates.

Myelin synthesis in vitro: a comparative study of central and peripheral nervous tissue.

Abstract— Brain, spinal cord and sciatic nerve from rats at different ages were incubated for 2 h in a medium containing [14C]acetate and [14C]leucine as the precursors for synthesis of lipids and proteins. Myelin was purified from the incubated tissues and the specific and total radioactivites of myelin lipids and protein were determined. The uptake of radioactive precursors decreased with increasing age up to 6 months of postnatal age, the decrease following the same pattern for the three types of myelin. After age 6 months the uptake of the protein and lipid precursors reached a plateau that persisted up to 18 months, the oldest postnatal age studied. The amount of myelin isolated and the total myelin lipids extracted from both the central and peripheral nervous systems increased continuously from age 25 days to 18 months after birth. Consequently we suggest that myelination is a process that continues during the whole life of the rat.The metabolic activity of peripheral nerve myelin was higher than myelin from the CNS at all ages studied. Although myelination in the sciatic nerve begins before that in brain and spinal cord, the three types of myelin apparently reach maturity at the same age. Lecithin exhibited the highest metabolic activity of the individual myelin lipids at all ages in both the central and peripheral nervous system. The metabolic activity of cholesterol in myelin from the 25‐day‐old rats was similar to that of lecithin but decreased to very low levels in myelin from the 18‐month‐old rats.

Myelin synthesis in two demyelinating mutations in mice

Tissue culture of cerebella of two demyelinating mutants, “dilute lethal” and “wabbler lethal,” revealed that cerebellar tissue of mice homozygous for these mutations, although grossly deficient in myelin in vivo, can synthesize myelin when explanted and maintained in vitro just as well as cerebella obtained from normal littermates. These observations are interpreted to mean that the block to myelin synthesis in these two mutants is probably extrinsic to the myelin-synthesizing cells.

A neurological mutation (msd) of the mouse causing a deficiency of myelin synthesis.

We describe a number of biochemical and pathological findings in a neurological syndrome which resulted from a mutation in the congenic resistant strain, B10.C(47N). The mutation, designated with the symbol msd, is sex-linked, recessive, and causes tremor, repeated seizures, and death of affected males at about 18–23 days of postnatal age. The earliest detectable clinical signs appear around 10 days of age. The CNS is markedly deficient in myelin. The white matter fiber tracts appear essentially as “negative images”. In contrast, the peripheral nerves are myelinated.

Effect of phenylalanine on protein synthesis in the developing rat brain.

1. Inhibition of the rate of incorporation of [(35)S]methionine into protein by phenylalanine was more effective in 18-day-old than in 8-day-old or adult rat brain. 2. Among the subcellular fractions incorporation of [(35)S]methionine into myelin proteins was most inhibited in 18-day-old rat brain. 3. Transport of [(35)S]methionine and [(14)C]leucine into the brain acid-soluble pool was significantly decreased in 18-day-old rats by phenylalanine (2mg/g body wt.). The decrease of the two amino acids in the acid-soluble pool equalled the inhibition of their rate of incorporation into the protein. 4. Under identical conditions, entry of [(14)C]glycine into the brain acid-soluble pool and incorporation into protein and uptake of [(14)C]acetate into lipid was not affected by phenylalanine. 5. It is proposed that decreased myelin synthesis seen in hyperphenylalaninaemia or phenylketonuria may be due to alteration of the free amino acid pool in the brain during the vulnerable period of brain development. Amyelination may be one of many causes of mental retardation seen in phenylketonuria.

An in vitro system for the study of myelin synthesis.

Abstract— A system for the study of short‐term myelin synthesis in spinal cord tissue in vitro with [U‐14C]glucose as a lipid and protein precursor is described. The rates of lipid and protein incorporation into myelin are age‐dependent, but do not appear to behave similarly. Uptake of labelled carbon is most rapid in monophosphoinositide and lecithin, and slowest in cerebroside sulphate. Myelin protein seems to retain more metabolic activity than does the lipid. These findings are interpreted as support for the unit membrane hypothesis for myelin rather than the subunit model.

The influence of malnutrition on the synthesis of myelin

the influence of malnutrition on the synthesis of myelin

Ultrastructure of peripheral nerve in metachromatic leucodystrophy

An electron microscopical study of two consecutive nerve biopsies from a patient with metachromatic leucodystrophy (sulphatide lipidosis) was made. The ultrastructural changes observed consisted of: a) irregular whorls of myelin. The myelin in the whorls showed a thickened, sometimes doubled, intraperiod line, which was barely visible in compact myelin; b) “inclusion bodies” up to 1 μ in diameter in the cytoplasm of Schwann cells. These had a lamellar structure, with stacked membranes 60 A apart; c) a “loose” pattern of the myelin in some nerve fibers, with loss of the intraperiod line, and d) presence of abnormally dense mitochondria with thickened cristae in Schwann cells. It is suggested that: a) the whorl formation and the ultrastructural abnormalities of the myelin in the whorls may be due to impaired myelin synthesis, and b) that the “inclusion bodies” may represent the accumulation of cerebroside sulfate in micellar aggregates. The “loose” pattern of myelin is considered artifactural until proven otherwise.

Aspects histo-enzymologiques de la maturation du système nerveux

Enzyme activities in the nervous system undergo considerable modifications in the course of maturation. These modifications affect not only the level of activity, but sometimes also the localization. Histochemical techniques reveal an enzyme-architectonic pattern in the nervous tissue whose development is different for the majority of enzymes studied. The evolution of these enzyme activities as a function of age is only an expression of the changes in metabolism which accompany maturation. We have shown by means of histochemical techniques the progressive post-natal development of non-specific acid phosphatases and carboxylic esterases in the cerebral cortex and cerebellum of the rat. We have shown also modifications in distribution of the esterases in the subcortical areas of the brain, A progressive elevation of succinate dehydrogenase (SD) and NADH (DPN) diaphorase (enzymes of the Krebs cycle) has been demonstrated histochemically by Friede in newborn rat brain. This period of elevation was observed to vary for each of the regions considered, and maturation was accompanied by changes in the carboxylic esterases similar to those shown by the dehydrogenases. Increased post-natal activity of acetylcholinesterase (AChE) (without change of distribution), and of monoamine oxidase (MAO), was noted by Gerebtzoff, Nachmias and Karki et al. On the whole, the maturation of those regions which are oldest from the phylogenetic point of view is more advanced than that of the newer regions. The maturation of the mesenchymal tissues of the brain, on the contrary, is completed at birth in the rat. The post-natal development of the different enzyme activities, particularly in the cerebral cortex, confirms biochemical data which indicate a considerable increase in metabolic processes which before birth, are essentially anaerobic and which, after birth, become aerobic with the establishment of functional activity in the cortex. There are well-established correlations between the levels of succinate dehydrogenase, acetylcholinesterase and MAO and the behaviour of the animals studied. Other enzymes of the cerebral parenchyma which appear to play a role in cellular proliferation, such as alkaline phosphatases and the pentose cycle enzymes, show a considerable fall in activity after birth. The increase in metabolic activity required by the synthesis of myelin is demonstrated histochemically by the temporary appearance, in the glia of the white matter, of an intense activity of non-specific carboxylic esterases, acid phosphatases, and of SD and NADH diaphorase. Histo-enzymological techniques allow studies of maturation on a regional scale far smaller than that possible with conventional biochemical techniques. They permit also a better understanding of variations in selective regional vulnerability of the nervous system as a function of age, and an understanding of the reason why identical pathological factors produce different changes in adult and developing brains.