Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress
| Autor: | Fei-Yang Tzou, Tsu-Yi Su, Chih-Chiang Chan, Yu-Han Yeh, Chung-Chih Liu, Wan-Syuan Lin, Ching-Hua Kuo, Han-Chun Kuo, Shu-Yi Huang, Yu-Lian Yu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Fatty Acid Desaturases rac1 GTP-Binding Protein Ceramide QH301-705.5 RAC1 medicine.disease_cause Ceramides General Biochemistry Genetics and Molecular Biology Retina 03 medical and health sciences chemistry.chemical_compound dihydroceramide 0302 clinical medicine Rac1 mislocalization Cell Line Tumor medicine Electroretinography Animals Drosophila Proteins Humans Point Mutation Biology (General) RNA Small Interfering chemistry.chemical_classification Neurons Reactive oxygen species Neurodegeneration neurodegeneration Membrane Proteins NADPH Oxidases Dihydroceramide desaturase Compartmentalization (psychology) medicine.disease Sphingolipid Cell biology Oxidative Stress 030104 developmental biology Drosophila melanogaster chemistry Gene Expression Regulation DEGS1 Photoreceptor Cells Invertebrate Reactive Oxygen Species 030217 neurology & neurosurgery Oxidative stress Protein Binding Signal Transduction |
| Zdroj: | Cell Reports, Vol 35, Iss 2, Pp 108972-(2021) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|