Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide level.

Abstract

Galactosylceramide (GalC) is the major sphingolipid of the myelin membrane. Mice lacking GalC due to ceramide galactosyltransferase (CGT) deficiency form unstable and functionally affected myelin and exhibit a progressive demyelination, accompanied by severe motor coordination deficits. In addition to oligodendrocytes, CGT is also expressed in other cells, e.g., neurons and astrocytes. We examined the possibility that lack of CGT in these cells contributes to the phenotype of CGT-deficient mice. Toward this aim, we generated transgenic mice expressing CGT under the control of oligodendrocyte-specific proteolipid protein (PLP) promoter and examined the possibility of a transgenic rescue of CGT-deficient mice. CGT-deficient mice expressing the PLP-CGT transgene did not show any behavioral abnormalities, normal myelin structure, and MBP levels. CGT activity as well as GalC and sulfatide levels of rescued mice were not significantly different from wild-type controls. Thus, transgenic rescue with the PLP-CGT transgene was apparently complete. In contrast to wild-type and rescued mice, PLP-CGT transgenic mice on a wild-type background exhibited significantly elevated CGT activity which directly correlated with an increase in non-hydroxy fatty acid (NFA)-GalC, but not alpha-hydroxy fatty acid (HFA)-GalC. HFA-GalC decreased in adult transgenic mice, indicating that NFA-GalC, but not HFA-GalC levels are limited by CGT activity. As a consequence, the total amount of GalC is unchanged over a rather wide range of CGT expression levels in the mouse brain. Our results indicate that loss of CGT in oligodendrocytes is exclusively responsible for the myelin structural deficits, demyelination, and behavioral abnormalities in CGT-deficient mice.

• Authors: Inge Zöller, Heinrich Büssow, Volkmar Gieselmann, Matthias Eckhardt
• Journal: Glia (Glia) Vol. 52 Issue 3 Pg. 190-8 (Nov 15 2005) ISSN: 0894-1491 [Print] United States
• PMID: 15968630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2005 Wiley-Liss, Inc.

Chemical References

• Fatty Acids
• Galactosylceramides
• Myelin Proteolipid Protein
• N-Acylsphingosine Galactosyltransferase

Topics

• Animals
• Brain (enzymology, metabolism)
• Brain Chemistry (genetics)
• Demyelinating Diseases (genetics, metabolism, physiopathology)
• Disease Models, Animal
• Fatty Acids (metabolism)
• Female
• Galactosylceramides (metabolism)
• Gene Expression Regulation (physiology)
• Male
• Mice
• Mice, Knockout
• Mice, Transgenic
• Microscopy, Electron, Transmission
• Myelin Proteolipid Protein (genetics)
• Myelin Sheath (genetics, metabolism, ultrastructure)
• N-Acylsphingosine Galactosyltransferase (biosynthesis, genetics)
• Nerve Fibers, Myelinated (metabolism, pathology, ultrastructure)
• Oligodendroglia (metabolism)
• Promoter Regions, Genetic (genetics)
• Transgenes (genetics)
• Up-Regulation (genetics)