The pathophysiological role of dihydroceramide desaturase in the nervous system.

Dihydroceramide desaturase 1 (DEGS1) converts dihydroceramide (dhCer) to ceramide (Cer) by inserting a C4-C5 trans (∆4E) double bond into the sphingoid backbone. Low DEGS activity causes accumulation of dihydroceramide and other dihydrosphingolipid species. Although dhCer and Cer are structurally very similar, their imbalances can have major consequences both in vitro and in vivo. Mutations in the human DEGS1 gene are known to cause severe neurological defects, such as hypomyelinating leukodystrophy. Likewise, inhibition of DEGS1 activity in fly and zebrafish models causes dhCer accumulation and subsequent neuronal dysfunction, suggesting that DEGS1 activity plays a conserved and critical role in the nervous system. Dihydrosphingolipids and their desaturated counterparts are known to control various essential processes, including autophagy, exosome biogenesis, ER stress, cell proliferation, and cell death. Furthermore, model membranes with either dihydrosphingolipids or sphingolipids exhibit different biophysical properties, including membrane permeability and packing, thermal stability, and lipid diffusion. However, the links between molecular properties, in vivo functional data, and clinical manifestations that underlie impaired DEGS1 function remain largely unresolved. In this review, we summarize the known biological and pathophysiological roles of dhCer and its derivative dihydrosphingolipid species in the nervous system, and we highlight several possible disease mechanisms that warrant further investigation.