TY  - JOUR
AU  - Ziegler, Anna B
AU  - Wesselmann, Cedrik
AU  - Beckschäfer, Konstantin
AU  - Wulf, Anna-Lena
AU  - Dhiman, Neena
AU  - Soba, Peter
AU  - Thiele, Christoph
AU  - Bauer, Reinhard
AU  - Tavosanis, Gaia
TI  - Individual lipid alterations at the origin of neuronal Ceramide Synthase defects.
JO  - PLoS Genetics
VL  - 21
IS  - 9
SN  - 1553-7390
CY  - San Francisco, Calif.
PB  - Public Library of Science
M1  - DZNE-2025-01155
SP  - e1011880
PY  - 2025
AB  - 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.
KW  - Animals
KW  - Lipid Metabolism: genetics
KW  - Ceramides: metabolism
KW  - Oxidoreductases: genetics
KW  - Oxidoreductases: metabolism
KW  - Drosophila melanogaster: genetics
KW  - Dendrites: metabolism
KW  - Dendrites: pathology
KW  - Dendrites: genetics
KW  - Drosophila Proteins: genetics
KW  - Drosophila Proteins: metabolism
KW  - Neurons: metabolism
KW  - Mutation
KW  - Lipidomics
KW  - Drosophila
KW  - dihydroceramide desaturase (NLM Chemicals)
KW  - Ceramides (NLM Chemicals)
KW  - Oxidoreductases (NLM Chemicals)
KW  - Drosophila Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40997116
DO  - DOI:10.1371/journal.pgen.1011880
UR  - https://pub.dzne.de/record/281537
ER  -