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@ARTICLE{Ziegler:281537,
      author       = {Ziegler, Anna B and Wesselmann, Cedrik and Beckschäfer,
                      Konstantin and Wulf, Anna-Lena and Dhiman, Neena and Soba,
                      Peter and Thiele, Christoph and Bauer, Reinhard and
                      Tavosanis, Gaia},
      title        = {{I}ndividual lipid alterations at the origin of neuronal
                      {C}eramide {S}ynthase defects.},
      journal      = {PLoS Genetics},
      volume       = {21},
      number       = {9},
      issn         = {1553-7390},
      address      = {San Francisco, Calif.},
      publisher    = {Public Library of Science},
      reportid     = {DZNE-2025-01155},
      pages        = {e1011880},
      year         = {2025},
      abstract     = {The brain is highly susceptible to disturbances in lipid
                      metabolism. Among the rare, genetically-linked epilepsies
                      Progressive Myoclonic Epilepsy Type 8 (PME8), associated
                      with the loss of Ceramide Synthase (CerS) activity, causes
                      epileptic symptoms accompanied by early onset of
                      neurodegenerative traits. The function of CerS is embedded
                      in a complex, conserved metabolic pathway, making it
                      difficult to identify the specific disease-relevant
                      alterations. Here, we show that the expression of an
                      enzymatically inactive cerS allele in Drosophila sensory
                      neurons yielded developmental and early onset dendrite loss.
                      Combining lipidomics and refined genetics with quantitative
                      analysis of neuronal morphology in cerS mutants, we
                      identified which lipids species are dysregulated and how
                      they affect neuronal morphology. In cerS mutants, long and
                      very-long acyl-chain C18-C24-ceramides were missing and
                      necessary for dendrite elaboration. In addition, the
                      substrate of CerS, (dh)S, and its metabolite (dh)S1P,
                      increased. Especially increasing (dh)S1P strongly reduces
                      dendritic complexity in cerS mutant neurons. Finally, we
                      performed in vivo experiments to cell-autonomously rescue
                      the morphological defects of cerS mutant neurons and report
                      that a complete rescue can only be achieved if the toxic
                      CerS substrate is converted to produce specific (C18-C24)
                      ceramides. Thus, despite the complex metabolic alterations,
                      our data provides essential information about the metabolic
                      origin of PME8 and delineates a potential therapeutic
                      avenue.},
      keywords     = {Animals / Lipid Metabolism: genetics / Ceramides:
                      metabolism / Oxidoreductases: genetics / Oxidoreductases:
                      metabolism / Drosophila melanogaster: genetics / Dendrites:
                      metabolism / Dendrites: pathology / Dendrites: genetics /
                      Drosophila Proteins: genetics / Drosophila Proteins:
                      metabolism / Neurons: metabolism / Mutation / Lipidomics /
                      Drosophila / dihydroceramide desaturase (NLM Chemicals) /
                      Ceramides (NLM Chemicals) / Oxidoreductases (NLM Chemicals)
                      / Drosophila Proteins (NLM Chemicals)},
      cin          = {AG Tavosanis},
      ddc          = {610},
      cid          = {I:(DE-2719)1013018},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40997116},
      doi          = {10.1371/journal.pgen.1011880},
      url          = {https://pub.dzne.de/record/281537},
}