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In vivo model to better understand neurodegeneration

Facing a camera, J. Thomas Hannich (biochemist, postdoc in the Riezman lab, UNIGE) presents his recent work and gives emphasis on the biochemical problem behind it. Denia Mellal (chemist, Roche Basel, former postdoc in the Zumbuehl lab, University of Fribourg) one comments with a few lines to explain the chemical approach used to solve the problem. They are from different disciplines but meet through chemical biology.


Perspective by Dr. Denia Mellal and Prof. Andreas Zumbuehl

Sphingolipids are ubiquitous components of eukaryotic cell membranes where they play important roles in intracellular signalling and in membrane structure. Their uncontrolled cellular production can lead to cell death and pathologies including auto-immune reactions, cancer, diabetes and neurodegeneration. In order to study the pathway of sphingolipids as a potential drug target and to understand their conserved roles, C. elegans nematode is used as a genetic model organism in which organism-specific C17 iso-branched-chain sphingoid bases are present.

We describe in our publication a convergent synthetic approach to a nematode-specific C17 iso-branched sphingoid base called sphinganine and its 1-deoxy analog called spisulosine from the erythro-1,2-amino alcohol intermediate. These sphingoid base analogues act as biochemical probes to better understand sphingolipid physiology in the context of intestinal development and cytoskeleton dynamics.

The project impressively shows species-specific structural differences in nema-todes and yeast (straight-chain C18 sphingoid base building blocks in mammals and budding yeast, iso-branched C17 in worms). Complementation experiments in C. elegans highlight the importance of iso-branch for biological activities as straight-chain sphingoid bases are non-functional in worms. This finding is currently exploited to kill parasitic nematodes which infect tomato plants. In budding yeast, iso-branched sphinganine shows strong toxicity.

Despite these structural differences, the sphingolipid function is still conserved in apoptosis, stress responses and intestinal development, which allows us to draw conclusions from the model system to the human disease. In this context, we have been able to highlight the toxicity of 1-deoxy sphingolipids by disrupting cytoskeletal structures. This has implications in the hereditary disease HSAN1A and other metabolic disorders including diabetes. Further studies in C. elegans are now required to elucidate the precise mechanisms of toxicity.

Go Further!

Hannich J. T., Mellal D., Feng S., Zumbuehl A., Riezman H., “Structure and conserved function of iso-branched sphingoid bases from the nematode Caenorhabditis elegans”, Chem. Sci., 2017, 8, 3676-3686. Read the publication

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