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000281537 041__ $$aEnglish
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000281537 1001_ $$0P:(DE-2719)2811714$$aZiegler, Anna B$$b0$$eFirst author
000281537 245__ $$aIndividual lipid alterations at the origin of neuronal Ceramide Synthase defects.
000281537 260__ $$aSan Francisco, Calif.$$bPublic Library of Science$$c2025
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000281537 520__ $$aThe 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.
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000281537 650_7 $$0EC 1.3.1.-$$2NLM Chemicals$$adihydroceramide desaturase
000281537 650_7 $$2NLM Chemicals$$aCeramides
000281537 650_7 $$0EC 1.-$$2NLM Chemicals$$aOxidoreductases
000281537 650_7 $$2NLM Chemicals$$aDrosophila Proteins
000281537 650_2 $$2MeSH$$aAnimals
000281537 650_2 $$2MeSH$$aLipid Metabolism: genetics
000281537 650_2 $$2MeSH$$aCeramides: metabolism
000281537 650_2 $$2MeSH$$aOxidoreductases: genetics
000281537 650_2 $$2MeSH$$aOxidoreductases: metabolism
000281537 650_2 $$2MeSH$$aDrosophila melanogaster: genetics
000281537 650_2 $$2MeSH$$aDendrites: metabolism
000281537 650_2 $$2MeSH$$aDendrites: pathology
000281537 650_2 $$2MeSH$$aDendrites: genetics
000281537 650_2 $$2MeSH$$aDrosophila Proteins: genetics
000281537 650_2 $$2MeSH$$aDrosophila Proteins: metabolism
000281537 650_2 $$2MeSH$$aNeurons: metabolism
000281537 650_2 $$2MeSH$$aMutation
000281537 650_2 $$2MeSH$$aLipidomics
000281537 650_2 $$2MeSH$$aDrosophila
000281537 7001_ $$aWesselmann, Cedrik$$b1
000281537 7001_ $$aBeckschäfer, Konstantin$$b2
000281537 7001_ $$aWulf, Anna-Lena$$b3
000281537 7001_ $$aDhiman, Neena$$b4
000281537 7001_ $$aSoba, Peter$$b5
000281537 7001_ $$aThiele, Christoph$$b6
000281537 7001_ $$aBauer, Reinhard$$b7
000281537 7001_ $$0P:(DE-2719)2810271$$aTavosanis, Gaia$$b8$$eLast author
000281537 773__ $$0PERI:(DE-600)2186725-2$$a10.1371/journal.pgen.1011880$$gVol. 21, no. 9, p. e1011880 -$$n9$$pe1011880$$tPLoS Genetics$$v21$$x1553-7390$$y2025
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