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You are here: Home Research Group Gieselmann Group Eckhardt Research


Biosynthesis and Function of Sphingolipids in Myelinating Cells and their Role in the Pathology of Human Leukodystrophies

Oligodendrocytes of the central nervous system and Schwann cells of the peripheral nervous system are highly specialized cells, producing large plasma membrane extensions, which form the myelin sheath. Myelin is essential for fast saltatory electrical conduction along axons. Diseases affecting the myelin sheath have therefore frequently devastating consequences for the patients.

The myelin sheath is unique in its protein and lipid composition. Myelin is especially enriched in two (glyco)sphingolipids: galactosylceramide and its derivative sulfatide (3-O-sulfogalactosylceramide). In the lysosomal storage disorder metachromatic leukodystrophy (MLD), sulfatide accumulates in the peripheral and central nervous system and various other organs. MLD patients suffer from a progressive demyelination and exhibit various neurological symptoms. The molecular basis of MLD is the inability to degrade sulfatide because of mutations in the ASA gene (or, less frequent, in its activator protein saposin B). The lysosomal enzyme arylsulfatase A (ASA) encoded by this gene degrades sulfatide and related sulfated galactolipids. In order to understand the molecular pathology of the disease, we have generated and are currently analyzing several transgenic mouse models.

Myelin sphingolipids are also unique in the length and modifications of their acyl residues. Changes in these structures significantly affect the properties of myelin and can cause diseases leading to demyelination and degeneration of axons. We are especially interested in one abundant modification: the 2-hydroxylation of the acyl residues of myelin sphingolipids. This modification is synthesized by the fatty acid 2-hydroxylase (FA2H). Mutations in the human FA2H gene causes a rare leukodystrophy with spastic paraplegia. The pathology of this disease, but also the physiological role the 2-hydroxylation, is studied using animal (FA2H-deficient mice) and cell culture models.



(Figure 1 shows electron micrographs of the corpus callosum of a normal mouse - with normal myelinated axons - and an ASA-deficient genetically modified to increase sulfatide storage - with a significant progressive loss of myelin)

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