University Hospital Zurich, Switzerland
DEGS1 activity is pivotal for CNS myelin formation
Sphingolipids (SLs) are not only structural components of membranes, but also serve as important signaling molecules involved in a variety of cellular processes including proliferation, differentiation, inflammation, apoptosis, and autophagy. Defects in sphingolipid metabolism predominantly affect the nervous system, which is highly enriched in SLs.
Recently, Δ4-dihydroceramide desaturase 1 (DEGS1) deficiency was identified as a novel cause for leukodystrophy in humans, and similar pathology was observed in DEGS1 deficient animal models. DES1 is a Δ4-sphingoid base desaturase that converts dihydroCeramide to Ceramide. Although the connection between reduced DES1 activity and leukodystrophy is well established, the underlying pathomechanism is not yet understood. DES1 deficiency causes several metabolic effects including the accumulation of dihydroSLs (dhSLs), concomitant reduction of canonical SLs and the appearance of a new atypical and probably toxic Δ14-sphingoid base.
Here we dissected the impact of these factors on myelination in a genetically and pharmacologically accessible murine neuron-glia co-culture model.
DES1 inhibition, by pharmacological inhibition (Fenretinide, GT11) or by siRNA resulted in a dose-dependent increase in dhSLs, a decrease in canonical SLs, and a concomitant reduction in myelination, whereas axon density was not affected. We further revealed that the reduction of canonical SLs by blocking de novo SL synthesis with myriocin had no obvious effect on myelination or axon density.
In summary, we showed that increased dhSL levels was sufficient to prevent myelination in an in vitro model, suggesting that this is the mechanism that mediates hypomyelination in DEGS1-dependent leukodystrophy.