論文 - 詳細
| RRC ID | 49294 |
|---|---|
| 著者 | Jung WH, Liu CC, Yu YL, Chang YC, Lien WY, Chao HC, Huang SY, Kuo CH, Ho HC, Chan CC. |
| タイトル | Lipophagy prevents activity-dependent neurodegeneration due to dihydroceramide accumulation in vivo. |
| ジャーナル | EMBO Rep |
| Abstract |
Dihydroceramide desaturases are evolutionarily conserved enzymes that convert dihydroceramide (dhCer) to ceramide (Cer). While elevated Cer levels cause neurodegenerative diseases, the neuronal activity of its direct precursor, dhCer, remains unclear. We show that knockout of the fly dhCer desaturase gene, infertile crescent (ifc), results in larval lethality with increased dhCer and decreased Cer levels. Light stimulation leads to ROS increase and apoptotic cell death in ifc-KO photoreceptors, resulting in activity-dependent neurodegeneration. Lipid-containing Atg8/LC3-positive puncta accumulate in ifc-KO photoreceptors, suggesting lipophagy activation. Further enhancing lipophagy reduces lipid droplet accumulation and rescues ifc-KO defects, indicating that lipophagy plays a protective role. Reducing dhCer synthesis prevents photoreceptor degeneration and rescues ifc-KO lethality, while supplementing downstream sphingolipids does not. These results pinpoint that dhCer accumulation is responsible for ifc-KO defects. Human dhCer desaturase rescues ifc-KO larval lethality, and rapamycin reverses defects caused by dhCer accumulation in human neuroblastoma cells, suggesting evolutionarily conserved functions. This study demonstrates a novel requirement for dhCer desaturase in neuronal maintenance in vivo and shows that lipophagy activation prevents activity-dependent degeneration caused by dhCer accumulation. |
| 巻・号 | 18(7) |
| ページ | 1150-1165 |
| 公開日 | 2017-7-1 |
| DOI | 10.15252/embr.201643480 |
| PII | embr.201643480 |
| PMID | 28507162 |
| PMC | PMC5494533 |
| MeSH | Animals Apoptosis Autophagy* Cell Line, Tumor Ceramides / analysis Ceramides / metabolism* Drosophila Drosophila Proteins / deficiency Drosophila Proteins / genetics Fatty Acid Desaturases / genetics Gene Knockout Techniques Humans Light / adverse effects Lipid Metabolism* Lipolysis Membrane Proteins / deficiency Membrane Proteins / genetics Neurodegenerative Diseases / prevention & control Photoreceptor Cells, Invertebrate / pathology Photoreceptor Cells, Invertebrate / radiation effects Sphingolipids / metabolism |
| IF | 7.497 |
| 引用数 | 11 |
| WOS 分野 | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ショウジョウバエ | CAS‐0003 |