https://scholars.lib.ntu.edu.tw/handle/123456789/507593
標題: | Lipophagy prevents activity-dependent neurodegeneration due to dihydroceramide accumulation in vivo | 作者: | Jung W.-H. Liu C.-C. Yu Y.-L. Chang Y.-C. Lien W.-Y. Chao H.-C. Huang S.-Y. CHING-HUA KUO Ho H.-C. CHIH-CHIANG CHAN |
公開日期: | 2017 | 出版社: | Wiley-VCH Verlag | 卷: | 18 | 期: | 7 | 起(迄)頁: | 1150-1165 | 來源出版物: | EMBO Reports | 摘要: | 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. ? 2017 The Authors |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-85019183717&doi=10.15252%2fembr.201643480&partnerID=40&md5=8f4af1f7dd227081aad57fa179e26578 https://scholars.lib.ntu.edu.tw/handle/123456789/507593 |
ISSN: | 1469-221X | DOI: | 10.15252/embr.201643480 | SDG/關鍵字: | ceramide; dihydroceramide; unclassified drug; acyl coenzyme A desaturase; ceramide; dihydroceramide; Drosophila protein; ifc protein, Drosophila; membrane protein; sphingolipid; apoptosis; Article; cellular distribution; clustered regularly interspaced short palindromic repeat; controlled study; electroretinogram; endosome; human; lethality; lipid storage; lipophagocytosis; nerve degeneration; neuroblastoma cell; neuroprotection; nonhuman; photoreceptor; photostimulation; priority journal; real time polymerase chain reaction; transmission electron microscopy; ultra performance liquid chromatography; animal; autophagy; deficiency; degenerative disease; Drosophila; gene knockout; genetics; invertebrate photoreceptor cell; light; lipid metabolism; lipolysis; metabolism; pathology; radiation response; tumor cell line; Animals; Apoptosis; Autophagy; Cell Line, Tumor; Ceramides; Drosophila; Drosophila Proteins; Fatty Acid Desaturases; Gene Knockout Techniques; Humans; Light; Lipid Metabolism; Lipolysis; Membrane Proteins; Neurodegenerative Diseases; Photoreceptor Cells, Invertebrate; Sphingolipids |
顯示於: | 生理學科所 |
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