Myelin structure and function

Myelin specific cerebrosides and sulfatides in the development and maintenance of the Myelin membrane, studied in the 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 nerve conductance and genetic diseases affecting the myelin sheath in dysmyelinoses, demyelination and inflammation, mostly autoimmune diseases.
Our genetic approach consists of the structural and functional dissection of myelin (oligodendrocyte and Schwann cell) specific membrane proteins and complex myelin membrane lipids by generating the respective null- allelic mouse mutant. The biochemical and cell biological analysis of their phenotypes has provided conclusive and often surprising insight and has broadened our view of the cellbiology of oligodendrocyte/Schwann cells.

Complementary to our studies on myelin integral membrane proteins we 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 conventional and conditional cgt mouse will allow to answer many important questions: the function in the development of the white matter of CNS, 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?

Literature

Haupt, W., Stoffel, W. (2004) Nerve conduction velocity measurements reveal the functional deficit in ceramide galactosyltrtansferase-deficient (cgt-/-) mice J.Neurol. Sci. 217:83-88

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

Stoffel, W., Bosio, A. (1997) Myelin glycolipids and their functions Curr.opinion in Neurobiol. 7, 654-660
Bosio, A., Binczek, E., 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

Bosio, A., Binczek, E., Le Beau, M. M., Fernald, A., 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

Bosio, A., Binczek, E., Stoffel, W. (1996) Molecular cloning and characerization of the mouse CGT gene encoding UDP-Glactose Ceramide-Galactosyl Transferase (Cerebroside Synthetase). Genomics, 35: 223-226

Schulte, S., Stoffel, W. (1993) Ceramide UDPgalactosyltransferase from myelinating rat brain: purification, cloning, and expression Proc.Natl. Acad. Sci. USA, 90, 10265-10269