Journal Article

DZNE-2025-01155

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.

Ziegler, A. B. (First author)DZNE* ; Wesselmann, C. ; Beckschäfer, K. ; Wulf, A.-L. ; Dhiman, N. ; Soba, P. ; Thiele, C. ; Bauer, R. ; Tavosanis, G. (Last author)DZNE*

2025
Public Library of Science San Francisco, Calif.

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Please use a persistent id in citations: doi:10.1371/journal.pgen.1011880

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.

Keyword(s): Animals (MeSH) ; Lipid Metabolism: genetics (MeSH) ; Ceramides: metabolism (MeSH) ; Oxidoreductases: genetics (MeSH) ; Oxidoreductases: metabolism (MeSH) ; Drosophila melanogaster: genetics (MeSH) ; Dendrites: metabolism (MeSH) ; Dendrites: pathology (MeSH) ; Dendrites: genetics (MeSH) ; Drosophila Proteins: genetics (MeSH) ; Drosophila Proteins: metabolism (MeSH) ; Neurons: metabolism (MeSH) ; Mutation (MeSH) ; Lipidomics (MeSH) ; Drosophila (MeSH) ; dihydroceramide desaturase ; Ceramides ; Oxidoreductases ; Drosophila Proteins

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Contributing Institute(s):

1. Dynamics of neuronal circuits (AG Tavosanis)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

Appears in the scientific report 2025

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