title: Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency.
abstract: Sphingolipids exhibit extreme functional and chemical diversity that is in part determined by their hydrophobic moiety, ceramide. In mammals, the fatty acyl chain length variation of ceramides is determined by six (dihydro)ceramide synthase (CerS) isoforms. Previously, we and others showed that mutations in the major neuron-specific CerS1, which synthesizes 18-carbon fatty acyl (C18) ceramide, cause elevation of long-chain base (LCB) substrates and decrease in C18 ceramide and derivatives in the brain, leading to neurodegeneration in mice and myoclonus epilepsy with dementia in humans. Whether LCB elevation or C18 ceramide reduction leads to neurodegeneration is unclear. Here, we ectopically expressed CerS2, a nonneuronal CerS producing C22-C24 ceramides, in neurons of Cers1-deficient mice. Surprisingly, the Cers1 mutant pathology was almost completely suppressed. Because CerS2 cannot replenish C18 ceramide, the rescue is likely a result of LCB reduction. Consistent with this hypothesis, we found that only LCBs, the substrates common for all of the CerS isoforms, but not ceramides and complex sphingolipids, were restored to the wild-type levels in the Cers2-rescued Cers1 mutant mouse brains. Furthermore, LCBs induced neurite fragmentation in cultured neurons at concentrations corresponding to the elevated levels in the CerS1-deficient brain. The strong association of LCB levels with neuronal survival both in vivo and in vitro suggests high-level accumulation of LCBs is a possible underlying cause of the CerS1 deficiency-induced neuronal death.
authors.affiliation: Department of Molecular and Cellular Medicine, Texas A&M Health Science Center, College Station, TX 77843;
authors.forename: Stefka D
authors.initials: SD
authors.lastname: Spassieva
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469;
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Ji
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609;
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Gable
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425;
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.affiliation: Department of Biochemistry and Molecular Biology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Dunn
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia/Augusta University, Augusta, GA 30912.
authors.forename: Erhard
authors.initials: E
authors.lastname: Bieberich
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609; lihong.zhao@jax.org.
authors.forename: Lihong
authors.initials: L
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002470:Cell Survival; D002518:Ceramides / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D008817:Mice, Mutant Strains; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013107:Sphingolipids / Q000096:biosynthesis / Q000235:genetics; D051049:Sphingosine N-Acyltransferase / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics
chemical_list: D002518:Ceramides; D008565:Membrane Proteins; D013107:Sphingolipids; C000609885:CerS1 protein, mouse; C580723:Cers2 protein, mouse; D051049:Sphingosine N-Acyltransferase
keywords: ceramide; ceramide synthase; long-chain base; neurodegeneration; sphingolipid