Individual lipid alterations at the origin of neuronal Ceramide Synthase defects

Area of Science:

• Neuroscience
• Metabolic disorders
• Genetics

Background:

• The brain's vulnerability to lipid metabolism disturbances.
• Progressive Myoclonic Epilepsy Type 8 (PME8), a rare genetic epilepsy linked to Ceramide Synthase (CerS) deficiency, presents with epilepsy and neurodegeneration.
• The complex metabolic pathway of CerS hinders identification of disease-specific alterations.

Purpose of the Study:

• To investigate the role of CerS in neuronal morphology and identify specific lipid dysregulations in PME8.
• To explore potential therapeutic strategies for PME8 by targeting CerS activity.

Main Methods:

• Utilized Drosophila sensory neurons expressing an inactive cerS allele.
• Employed lipidomics, quantitative analysis of neuronal morphology, and refined genetics.
• Performed in vivo cell-autonomous rescue experiments.

Main Results:

• Loss of CerS activity led to developmental and early-onset dendrite loss in Drosophila neurons.
• Identified a deficiency in long and very-long acyl-chain ceramides (C18-C24) and an accumulation of the CerS substrate (dh)S and its metabolite (dh)S1P.
• Demonstrated that elevated (dh)S1P significantly reduces dendritic complexity.
• Achieved complete rescue of morphological defects only when the CerS substrate was converted to specific (C18-C24) ceramides.

Conclusions:

• Specific long-chain ceramides (C18-C24) are crucial for dendrite elaboration.
• Accumulation of the CerS substrate (dh)S1P contributes to neurodegeneration in PME8.
• Targeting CerS substrate conversion to produce specific ceramides offers a potential therapeutic avenue for PME8.