RRC ID 49294
Author Jung WH, Liu CC, Yu YL, Chang YC, Lien WY, Chao HC, Huang SY, Kuo CH, Ho HC, Chan CC.
Title Lipophagy prevents activity-dependent neurodegeneration due to dihydroceramide accumulation in vivo.
Journal 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.
Volume 18(7)
Pages 1150-1165
Published 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
Times Cited 11
WOS Category BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
Drosophila CAS‐0003