| RRC ID |
70814
|
| 著者 |
Tzou FY, Su TY, Lin WS, Kuo HC, Yu YL, Yeh YH, Liu CC, Kuo CH, Huang SY, Chan CC.
|
| タイトル |
Dihydroceramide desaturase regulates the compartmentalization of Rac1 for neuronal oxidative stress.
|
| ジャーナル |
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.
|
| 巻・号 |
35(2)
|
| ページ |
108972
|
| 公開日 |
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
|
| リソース情報 |
| ショウジョウバエ |
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