Güntert T Hänggi P Othman A Suriyanarayanan S Sonda S Zuellig RA Hornemann T Ogunshola OO 2016 1-Deoxysphingolipids (1-deoxySL) are atypical and neurotoxic sphingolipids formed by alternate substrate usage of the enzyme serine-palmitoyltransferase. Pathologically increased 1-deoxySL formation causes hereditary sensory and autosomal neuropathy type 1 (HSAN1) - a progressive peripheral axonopathy. However, the underlying molecular mechanisms by which 1-deoxySL acts are unknown. Herein we studied the effect of 1-deoxysphinganine (1-deoxySA) and its canonical counterpart sphinganine (SA) in aged cultured neurons comparing their outcome on cell survival and cytoskeleton integrity. 1-deoxySA caused rapid neuronal cytoskeleton disruption and modulated important cytoskeletal regulatory and associated components including Rac1, Ezrin and insulin receptor substrate 53. We show that 1-deoxySA is internalized and metabolized downstream to 1-deoxydihydroceramide since inhibition of ceramide synthase protected neurons from 1-deoxySA-mediated cell death. In addition, 1-deoxySA reduced protein levels of N-methyl-d-aspartate receptor (NMDAR) subunit GluN2B, the postsynaptic density protein 95 and induced cleavage of p35 to p25. Notably, blocking NMDAR activation by MK-801 or memantine significantly prevented 1-deoxySA neurotoxicity. Functional studies of differentiating primary neurons via the patch-clamp technique demonstrated that 1-deoxySA irreversibly depolarizes the neuronal membrane potential in an age-dependent manner. Notably, only neuronal cells that displayed functional NMDAR- and NMDA-induced whole-cell currents responded to 1-deoxySA treatment. Furthermore, pre-exposure to the non-competitive antagonist MK-801 blocked the current response of NMDA and glycine, as well as 1-deoxySA. We conclude that 1-deoxySA-induced neurotoxicity compromises cytoskeletal stability and targets NMDAR signaling in an age-dependent manner. Thus stabilization of cytoskeletal structures and/or inhibition of glutamate receptors could be a potential therapeutic approach to prevent 1-deoxySA-induced neurodegeneration. https://sonar.ch/global/documents/143455 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.neuropharm.2016.03.033 info:eu-repo/semantics/altIdentifier/pmid/27016021 Neuropharmacology. - 2016 Cytoskeleton Hereditary sensory and autosomal neuropathy type 1 Lipid metabolism NMDA receptor Rac1 Animals Cell Line, Tumor Cerebral Cortex Cytoskeleton Disks Large Homolog 4 Protein Dizocilpine Maleate Dose-Response Relationship, Drug Excitatory Amino Acid Antagonists Glycine Humans Memantine Membrane Potentials Mice, Inbred C57BL N-Methylaspartate Neurons Neuroprotective Agents Receptors, N-Methyl-D-Aspartate Signal Transduction Sphingolipids Sphingosine rac1 GTP-Binding Protein 1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling. http://purl.org/coar/resource_type/c_6501