Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

Stefka D. Spassieva, Xiaojie Ji, Ye Liu, Kenneth Gable, Jacek Bielawski, Teresa M. Dunn, Erhard Bieberich, Lihong Zhao

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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.

Original languageEnglish
Pages (from-to)5928-5933
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
StatePublished - May 24 2016

Bibliographical note

Funding Information:
We would like to thank Dr. Patsy M. Nishina for her tremendous support. We thank The Jackson Laboratory Scientific Services, including Genetic Engineering Technologies, Sequencing, Histology and Imaging Sciences, and Multimedia Services, for its services and the Medical University of South Carolina Lipidomics Core for the mass spectrometry analyses. We also thank Drs. Patsy M. Nishina, Jürgen K. Naggert, and Robert W. Burgess for editorial comments and Ms. Alicia Valenzuela for advice on nomenclature. We thank Drs. Guanghu Wang and Michael Dinkins (E.B. laboratory) for cultivation of neurons. This work is supported by NIH Grant NS075447 (to L.Z.) and in part by pilot research funding from Hollings Cancer Center's Cancer Center Support Grant P30 CA138313 and pilot research funding from COBRE for Lipidomics and Pathobiology NIH Grant 5P30GM103339-03 at the Medical University of South Carolina (to S.D.S.). The Jackson Laboratory Scientific Services is supported by NIH Grant CA034196. Partial funding by NIH Grant R01 AG034389 (to E.B.) and NIH Grant HD080181 (to T.M.D.) are acknowledged


  • Ceramide
  • Ceramide synthase
  • Long-chain base
  • Neurodegeneration
  • Sphingolipid

ASJC Scopus subject areas

  • General


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