The role of Ceramide Synthase for neuronal maintenance and function

• Applicant: Dr. Anna Barbara Ziegler
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455143368

Lipids are fundamental molecules implicated in a wide range of biological processes. They can be used as energy substrate, building block for membranes or bioactive signaling molecules. Neurons are particularly vulnerable to alterations in their lipid homeostasis. Defects in lipid production or degradation cause neuromorphological changes such as loss of dendritic complexity or denervation and can lead to functional impairments for example trough reduced neurotransmitter release or excitotoxicity (Hussain et al., 2019; Tracy et al., 2018; Ziegler et al., 2018). Point mutations within Ceramide synthase 1 (CerS1), a key enzyme in ceramide production, have been identified in patients suffering from Progressive Myoclonic Epilepsy type 8 (PME8). Ceramides belong to the class of sphingolipids and serve as precursors of complex membranous sphingolipids. In addition, ceramide and its non acylated metabolites, the so-called long chain sphingoid bases (LCBs), have key functions in signaling events regulating a variety of biological processes including apoptosis, survival or differentiation (Hannun et al., 2018). However, it is not fully understood how alterations in ceramide metabolic pathways affect neuronal function and maintenance. My preliminary data show that lack of CerS enzymatic function leads to dendrite degeneration and causes axonal defects. Within the frame of this proposal the molecular consequences of CerS malfunctioning will be investigated in single cell resolution and it’s tasks for neuronal maintenance and function will be elucidated from different angles. Here, at first the enzymatic function of CerS will be looked at. It will be studied how the lack of CerS activity affects neurobiological functions including neuronal excitation levels, synapse stability and signal transmission. Next, alterations within ceramide and LCB levels and composition will be measured. Alterations in the level of specific lipids will be linked to cell-biological changes such as defects in autophagic and endocytic pathways, mitochondrial dysfunction, or the onset or stress response pathways. Finally, CerS have a dual function. Within the N-terminal region they harbor a homeodomain of less studied function. Here, I have strong evidence suggesting interplay between the homeodomain function and the regulation of endosomal/lysosomal degradation processes. This proposed interconnection will be solidified and the down-stream effects leading to altered neuronal morphology and putatively also neuronal function investigated. In summary this study will provide a detailed analysis of interconnections between a specific lipid synthetizing pathway and its role within neuronal maintenance and function. It will help to gain better understanding of diseases such as PME8, in which lipid metabolic pathways are affected. Additionally, this study will bring new knowledge about the yet unexplored neuronal function of the CerS homeodomain.

• DFG Programme: Research Grants