• neurodegenerative disease

To investigate aspects of neurodegenerative diseases associated with perturbations of sphingolipid metabolism, phenotypes of the fly dihydroceramide desaturase gene, ifc, have been characterized. Classical loss-of-function mutations, an amorphic allele created by targeted recombination, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\ifc. There are two orthologous genes in human, DEGS1 and DEGS2.

Several UAS constructs of the wild-type human Hsap\DEGS1 gene have been introduced into flies; heterologous rescue (functional complementation) of the amorphic ifc larval lethal phenotype has been demonstrated.

Animals homozygous for an amorphic allele of Dmel\ifc exhibit larval lethality with increased dihydroceramide and decreased ceramide levels. Using homozygous clones induced in the eye, it was determined that light stimulation leads to ROS increase and apoptotic cell death of the ifc-deficient photoreceptors, resulting in activity-dependent neurodegeneration. Genetic and chemical-supplementation experiments support the hypothesis that both phenotypes are due to the increased levels of dihydroceramide, rather than reduced levels of ceramide.

It has recently been determined that an autosomal recessive disease designated leukodystrophy, hypomyelinating, 18 (HLD18) is associated with one of the two human dihydroceramide desaturase genes, DEGS1 (MIM:618404, FBhh0001141).

[updated Nov. 2019 by FlyBase; FBrf0222196]