title: Ceramides And Stress Signalling Intersect With Autophagic Defects In Neurodegenerative Drosophila blue cheese (bchs) Mutants.
abstract: Sphingolipid metabolites are involved in the regulation of autophagy, a degradative recycling process that is required to prevent neuronal degeneration. Drosophila blue cheese mutants neurodegenerate due to perturbations in autophagic flux, and consequent accumulation of ubiquitinated aggregates. Here, we demonstrate that blue cheese mutant brains exhibit an elevation in total ceramide levels; surprisingly, however, degeneration is ameliorated when the pool of available ceramides is further increased, and exacerbated when ceramide levels are decreased by altering sphingolipid catabolism or blocking de novo synthesis. Exogenous ceramide is seen to accumulate in autophagosomes, which are fewer in number and show less efficient clearance in blue cheese mutant neurons. Sphingolipid metabolism is also shifted away from salvage toward de novo pathways, while pro-growth Akt and MAP pathways are down-regulated, and ER stress is increased. All these defects are reversed under genetic rescue conditions that increase ceramide generation from salvage pathways. This constellation of effects suggests a possible mechanism whereby the observed deficit in a potentially ceramide-releasing autophagic pathway impedes survival signaling and exacerbates neuronal death.
authors.affiliation: National Centre for Biological Sciences; Tata Institute of Fundamental Research; Bangalore, Karnataka, 560065; India.|Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Sarita
authors.initials: S
authors.lastname: Hebbar
authors.affiliation: National Centre for Biological Sciences; Tata Institute of Fundamental Research; Bangalore, Karnataka, 560065; India.|School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.
authors.forename: Ishtapran
authors.initials: I
authors.lastname: Sahoo
authors.affiliation: School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.
authors.forename: Artur
authors.initials: A
authors.lastname: Matysik
authors.affiliation: School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.|Biotechnology Center (BIOTEC), Technical University of Dresden, Dresden, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Argudo Garcia
authors.affiliation: School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.
authors.forename: Kathleen Amy
authors.initials: KA
authors.lastname: Osborne
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.|ABSciex, Darmstadt, Germany.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Papan
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Federico
authors.initials: F
authors.lastname: Torta
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Narayanaswamy
authors.affiliation: School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.
authors.forename: Xiu Hui
authors.initials: XH
authors.lastname: Fun
authors.affiliation: Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Wenk
authors.affiliation: Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
authors.forename: Andrej
authors.initials: A
authors.lastname: Shevchenko
authors.affiliation: National Centre for Biological Sciences; Tata Institute of Fundamental Research; Bangalore, Karnataka, 560065; India.|Research Center Borstel, Borstel, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Schwudke
authors.affiliation: School of Biological Sciences; Nanyang Technological University; Singapore, 637551, Republic of Singapore.|Biotechnology Center (BIOTEC), Technical University of Dresden, Dresden, Germany.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kraut
mesh_terms: D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D055572:Ceramidases / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D050356:Lipid Metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009410:Nerve Degeneration / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D002518:Ceramides; D029721:Drosophila Proteins; D009419:Nerve Tissue Proteins; D013107:Sphingolipids; C472019:bchs protein, Drosophila; D051057:Proto-Oncogene Proteins c-akt; D013108:Sphingomyelin Phosphodiesterase; D055572:Ceramidases