RRC ID 70814
Author Tzou FY, Su TY, Lin WS, Kuo HC, Yu YL, Yeh YH, Liu CC, Kuo CH, Huang SY, Chan CC.
Title Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress.
Journal Cell Rep
Abstract Disruption of sphingolipid homeostasis is known to cause neurological disorders, but the mechanisms by which specific sphingolipid species modulate pathogenesis remain unclear. The last step of de novo sphingolipid synthesis is the conversion of dihydroceramide to ceramide by dihydroceramide desaturase (human DEGS1; Drosophila Ifc). Loss of ifc leads to dihydroceramide accumulation, oxidative stress, and photoreceptor degeneration, whereas human DEGS1 variants are associated with leukodystrophy and neuropathy. In this work, we demonstrate that DEGS1/ifc regulates Rac1 compartmentalization in neuronal cells and that dihydroceramide alters the association of active Rac1 with organelle-mimicking membranes. We further identify the Rac1-NADPH oxidase (NOX) complex as the major cause of reactive oxygen species (ROS) accumulation in ifc-knockout (ifc-KO) photoreceptors and in SH-SY5Y cells with the leukodystrophy-associated DEGS1H132R variant. Suppression of Rac1-NOX activity rescues degeneration of ifc-KO photoreceptors and ameliorates oxidative stress in DEGS1H132R-carrying cells. Therefore, we conclude that DEGS1/ifc deficiency causes dihydroceramide accumulation, resulting in Rac1 mislocalization and NOX-dependent neurodegeneration.
Volume 35(2)
Pages 108972
Published 2021-4-13
DOI 10.1016/j.celrep.2021.108972
PII S2211-1247(21)00286-2
PMID 33852856
MeSH Animals Cell Line, Tumor Ceramides / metabolism Drosophila Proteins / deficiency Drosophila Proteins / genetics* Drosophila melanogaster / genetics* Drosophila melanogaster / metabolism Electroretinography Fatty Acid Desaturases / antagonists & inhibitors Fatty Acid Desaturases / genetics* Fatty Acid Desaturases / metabolism Gene Expression Regulation Humans Membrane Proteins / deficiency Membrane Proteins / genetics* NADPH Oxidases / genetics* NADPH Oxidases / metabolism Neurons / metabolism Neurons / pathology Oxidative Stress Photoreceptor Cells, Invertebrate / metabolism Photoreceptor Cells, Invertebrate / pathology Point Mutation Protein Binding RNA, Small Interfering / genetics RNA, Small Interfering / metabolism Reactive Oxygen Species / metabolism Retina / metabolism Retina / pathology Signal Transduction rac1 GTP-Binding Protein / genetics* rac1 GTP-Binding Protein / metabolism
IF 8.109