Laboratory of Molecular Neuroscience   printer friendly

Ceramide galactosyl transferase

The role of myelin specific cerebrosides and sulfatides in the development and maintenance of the myelin structure and function studied in the conditional ceramide-galactosyl-transferase (cgt-/-)null allelic mouse

Understanding the structure-function relationship between myelin membrane integral proteins and the lipid bilayer on one hand and the myelin sheath and the axon on the other hand is a pivotal demand for understanding the molecular events in genetic diseases affecting the myelin sheath, dysmyelinoses, demyelination and inflammation, mostly autoimmune diseases of myelin.

Our experimental approach is a genetic approach, which consists of the structural and functional dissection of individual oligodendrocyte and Schwann cell specific membrane proteins and complex myelin lipids by generating the respective null- allelic mouse mutant. In the past, the biochemical and cell biological analysis of their phenotypes has provided conclusive and often surprising insight and has broadened our view of the neurobiology of the oligodendrocyte/Schwann cell field.

WWe have focused on the role of the two main lipid constituents of the myelin membrane of CNS as well as PNS, galactosylceramide (GalC) and sulfatides (sGalC). We have generated the conventional ceramide galactosyl transferase (CGT) deficient (cgt-/-) mouse mutant. The loss of the key enzyme CGT caused the total absence of these two glycosphingolipids. Our biochemical, cell biological and electrophysiological analyses provided a molecular understanding of the neuropathological symptoms, whole body tremor, loss of saltatory conduction, seizures, abnormal CNS myelination of axons and the early death after the myelination period. The short life span (about six weeks) of the cgt-/- mouse does not allow the answer to important questions related to the function of CGT in the development of the white matter of CNS, what are the functions of CGT and its synthesis products GalC and sGalC in the maintenance of the axonal myelin sheath in the fully developed white matter during development to adulthood of the mouse. Do the dominant oligodendrocyte surface markers GalC and sGalC play a role in autoimmune diseases, what does the loss of these lipid structures in the cgt-/- mouse mean for myelin stability in autoimmune attacks of the myelin sheath in EAE models?

We are currently generating the inducible conventional cgt-/- null mutant mouse.


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Figure 1: Comparison of wt- and cgt-/- mouse.


References
  1. Haupt,W. and Stoffel, W, 2004 Nerve conduction velocity measurements reveal the functional deficit in ceramide galactosyltrtansferase-deficient (cgt-/-) mice J.Neurol. Sci. 217:83-88
  2. Spörkel , O., Uschkureit, T, Büssow, H. and Stoffel, W. 2002. Oligodendrocytes Expressing Exclusively the DM20 Isoform of the Proteolipid Protein Gene: Myelination and Development, GLIA 37, 19-30.
  3. Stoffel, W., 2002. GalCer Synthase (Ceramide Galactosyltransferase, CGT) in Handbook of Glycosyltransferases and Related Genes, pp. 51-60, ed. N.Tanigoushi, K. Honke and M. Fukuda, Springer New York
  4. Simons, M., Kramer, E.M., Thiele, C., Stoffel, W., Trotter, J. 2000 Assembly of myelin by association of poteolipid protein with cholesterol- and galactosylceramide-rich membrane domains J. Cell Biol. 151, 143-154
  5. Bosio, A., Büssow, H., Adam, J. Stoffel, W. 1998 Galactosphingolipids and axono-glial interaction in myelin of the central nervous system Cell Tissue Res. 292, 199-210
  6. Stoffel, W. and Bosio, A. 1997. Myelin glycolipids and their functions Curr.opinion in Neurobiol. 7, 654-660
  7. Bosio, A., Binczek, E., and Stoffel, W. (1996) Functional breakdown of the lipid bilayer of the myelin membrane in central and peripheral nervous system by disrupted galactocerebroside synthesis. Proc. Natl. Acad. Sci. USA 93, 13280-13285.
  8. Bosio, A., Binczek, E., Le Beau, M. M., Fernald, A., and Stoffel, W. (1996). The human gene CGT encoding the UDP-galactose ceramide galactosyl transferase (cerebroside synthase): cloning, characterization, and assignment to human chromosome 4, band q26. Genomics 34: 69-75.
  9. A. Bosio, M. Binczek, W. Stoffel (1996) Molecular cloning and characerization of the mouse CGT gene encoding UDP-Glactose Ceramide-Galactosyl Transferase (Cerebroside Synthetase). Genomics, 35: 223-226
  10. S. Schulte, W. Stoffel Ceramide UDPgalactosyltransferase from myelinating rat brain: purification, cloning, and expression Proc.Natl. Acad. Sci. USA, 90, 10265-10269 (1993)


July 12, 2011
Center for Biochemistry, Joseph-Stelzmann-Straße 52, D50931 Cologne
Suggestions and wishes: Budi Tunggal
Voice: +49 221 4786930, Fax: +49 221 4786979
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