Functions of sphingolipid metabolism in mammals--lessons from genetic defects.

International audienceMuch is known about the pathways that control the biosynthesis, transport and degradation of sphingolipids. During the last two decades, considerable progress has been made regarding the roles this complex group of lipids play in maintaining membrane integrity and modulating responses to numerous signals. Further novel insights have been provided by the analysis of newly discovered genetic diseases in humans as well as in animal models harboring mutations in the genes whose products control sphingolipid metabolism and action. Through the description of the phenotypic consequences of genetic defects resulting in the loss of activity of the many proteins that synthesize, transport, bind, or degrade sphingolipids, this review summarizes the (patho)physiological functions of these lipids

Astrocytic p38 MAPK drives NMDA receptor-dependent long-term depression and modulates long-term memory

NMDA receptor-dependent long-term depression (LTD) in the hippocampus is a well-known form of synaptic plasticity that has been linked to different cognitive functions. The core mechanism for this form of plasticity is thought to be entirely neuronal. However, we now demonstrate that astrocytic activity drives LTD at CA3-CA1 synapses. We have found that LTD induction enhances astrocyte-to-neuron communication mediated by glutamate, and that Ca signaling and SNARE-dependent vesicular release from the astrocyte are required for LTD expression. In addition, using optogenetic techniques, we show that low-frequency astrocytic activation, in the absence of presynaptic activity, is sufficient to induce postsynaptic AMPA receptor removal and LTD expression. Using cell-type-specific gene deletion, we show that astrocytic p38α MAPK is required for the increased astrocytic glutamate release and astrocyte-to-neuron communication during low-frequency stimulation. Accordingly, removal of astrocytic (but not neuronal) p38α abolishes LTD expression. Finally, this mechanism modulates long-term memory in vivo.We thank the personnel at the fluorescence microscopy facility of the CBMSO (SMOC) for their expert technical assistance. We also thank Alfonso Araque, Carlos Dotti, Liset Menéndez de la Prida, Manuel Valero, Sara Mederos and Gertrudis Perea for expert advice and critical reading of the manuscript, and Simon Arthur (University of Dundee, UK) for the p38α knockout mice. We thank Godwin K. Dogbevia, Artur Luzgin, and Maria Calleja for technical help with molecular biology, virus purifications and characterization of AAV2/1-PGFAP-TeTxLC-2A-mKO. This work was supported by grants from the Spanish Ministry of Economy and Competitiveness to J.A.E. (SAF2015-72988-EXP, PCIN-2016-095 and SAF2017-86983-R), to M.N. (SAF2014-58598-JIN; RYC-2016-20414), to M.I.C. (IJCI-2015-25507), and to J.A.E. and A.R.N. (CSD2010-0045). M.N. was also funded from BBVA Foundation and L'Oreal Unesco “For Women in Science”

New perspectives on the role of sphingosine 1-phosphate in cancer

In this chapter, we review the latest developments concerning the role of sphingosine 1-phosphate (S1P) in cancer. Particular focus is paid to the role of sphingosine kinases 1 and 2, S1P lyase and S1P-dependent signalling networks in both solid tumours and haematological cancer. The potential of this S1P-dependent pathophysiology as a therapeutic target for the treatment of cancer is also discussed