Myelination in the Absence of Galactocerebroside and Sulfatide: Normal Structure with Abnormal Function and Regional Instability

Coetzee, Timothy; Fujita, Nobuya; Dupree, Jeffrey L.; Shi, Riyi; Blight, Andrew R.; Suzuki, Kinuko; Suzuki, Kazuyuki; Popko, Brian

doi:10.1016/s0092-8674(00)80093-8

Cited by 571 publications

(552 citation statements)

References 58 publications

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“…Furthermore, elevated levels of lactosylceramides with the concomitant reduction of gangliosides may alter plasma membrane organization and cellular activities, as described in refs. 29-31. Deletion of members of the gala-series of glycosphingolipids, which include galacosylceramide and sulfatide, produce mice with phenotypes remarkably similar to the double-null Galgt1 Siat9 mice (16,32). Furthermore, these glycolipids play key roles in axonal-glia interactions and in formation of the node of Ranvier (33).…”

Section: Discussionmentioning

confidence: 99%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

211

160

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Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.glycosphingolipid ͉ neurodegeneration ͉ glycosyltransferase

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Section: Discussionmentioning

confidence: 99%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

211

160

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“…Figure 5b shows the MS/MS spectrum of a sulfatide sphingolipid (6 Scheme 1) at m/z 888. Sulfated galactocerebrosides (sulfatides), known especially for their role in the myelin sheath of the nervous system [47], differ from the lipids discussed thus far in that they do not contain a glycerol-phosphate backbone but instead possess a sphingosine base. A fatty acid chain, which can be unsaturated and/or hydroxylated, is attached to the nitrogen of the sphingosine backbone via an amide bond.…”

Section: Analysis Of Complex Mixturesmentioning

confidence: 99%

Desorption electrospray ionization (DESI) mass spectrometry and tandem mass spectrometry (MS/MS) of phospholipids and sphingolipids: Ionization, adduct formation, and fragmentation

Manicke

Wiseman

Ifa

et al. 2008

J. Am. Soc. Mass Spectrom.

164

138

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Desorption electrospray ionization (DESI) mass spectrometry was evaluated for the characterization of glycerophospholipid standards, including glycerophosphocholine (GPCho), glycerophosphoglycerol (GPGro), glycerophosphoethanolamine (GPEtn), glycerophosphoserine (GPSer), glycerophosphoinositol (GPIns), cardiolipin (CL), and sphingolipid standards, including sulfatides (ST) and sphingomyelin (SM). Of specific interest were the effects of surface and solvent composition on signal stability and intensity, along with the ions observed in the full scan mode and the fragmentations seen upon collisional activation for each of the above classes. These experiments were performed without the addition of matrix compounds to the sample and were conducted in the free ambient environment at atmospheric pressure. The compounds GPSer, GPGro, GPIns, ST, and CL were best analyzed in the negative ion mode while PE was ionized efficiently in both positive and negative ion modes. SM and GPCho, which typically generate more abundant ions in the positive ion mode, could be analyzed in the negative ion mode by the addition of anionic reagents such as acetate to the spray solvent. Full scan DESI mass spectra and tandem (MS/MS) spectra for this representative set of physiological phospho/sphingolipids are presented. Similarities with other ionization methods in terms of fragmentation behavior were strong, although ambient ionization of untreated samples is only available with DESI. The effect of surface and solvent properties on signal intensity and stability were determined by depositing standard compounds on several different surfaces and analyzing with various proportions of methanol in the aqueous spray. Analysis was extended to complex mixtures of phospholipids and sphingolipids by examining the total lipid extract of porcine brain and by direct analysis of rat brain cryotome sections. These types of mixture analyses and molecular imaging studies are likely to represent major areas of application of DESI. (J

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“…Additionally, a comparative proteomic approach was used to compare the expression of proteins in myelin from wild-type and genetically modified CGT-null mice (32,33). These mice are unable to express two key myelin glycosphingolipids, galactocerebroside and sulfatide.…”

Section: Identification and Mapping Of Myelin Proteinsmentioning

confidence: 99%

Proteomic mapping provides powerful insights into functional myelin biology

Taylor

Marta

Claycomb

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

108

107

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Myelin is a dynamic, functionally active membrane necessary for rapid action potential conduction, axon survival, and cytoarchitecture. The number of debilitating neurological disorders that occur when myelin is disrupted emphasizes its importance. Using highresolution 2D gel electrophoresis, mass spectrometry, and immunoblotting, we have developed an extensive proteomic map of proteins present in myelin, identifying 98 proteins corresponding to at least 130 of the Ϸ200 spots on the map. This proteomic map has been applied to analyses of the localization and function of selected proteins, providing a powerful tool to investigate the diverse functions of myelin.M yelin is a dynamic, functionally active membrane (1), the loss or damage of which results in serious neurological disorders including leukodystrophies, central and peripheral neuropathies, and inflammatory demyelinating diseases such as multiple sclerosis (2-4). Rapid and efficient action potential conduction in the nervous system depends on myelin, which traditionally has been viewed as a passive contributor to conduction by increasing internodal membrane resistance and decreasing membrane capacitance (5). However, recent work has revealed additional active roles for myelin in nervous system development and function. For example, myelin regulates axon diameter and the formation of axon microtubular networks, and it is a key player in ion channel clustering at nodes of Ranvier (6-11). In return, the axon regulates myelin gene expression (12) and oligodendrocyte survival (13). The functional coupling of myelin and axons is further illustrated by the transfer of phospholipids (14) and N-acetylaspartate (15) from the axon to the myelin sheath.A major impediment to understanding the active biological functions of myelin is the relative lack of myelin proteins that have been described and characterized. Thus, we have undertaken an extensive proteomic analysis of central nervous system myelin, developed a 2D PAGE map of myelin proteins, identified 98 of these proteins, and illustrated the power and utility of this approach through specific applications of comparative proteomics. For example, a comparison of CNS and peripheral nervous system (PNS) myelin proteins has revealed a previously undescribed component of Schwann cell microvilli, a proteomic matching of myelin from normal and genetically modified mice lacking key myelin lipids has demonstrated a dramatic reduction of two newly recognized myelin protein kinases, and an application of the map to a neuroimmunological analysis of demyelinating disease has identified a signaling mechanism (16).

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Myelination in the Absence of Galactocerebroside and Sulfatide: Normal Structure with Abnormal Function and Regional Instability

Cited by 571 publications

References 58 publications

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Desorption electrospray ionization (DESI) mass spectrometry and tandem mass spectrometry (MS/MS) of phospholipids and sphingolipids: Ionization, adduct formation, and fragmentation

Proteomic mapping provides powerful insights into functional myelin biology

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