title: 1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling.
abstract: 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.
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Güntert
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Hänggi
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
authors.forename: Alaa
authors.initials: A
authors.lastname: Othman
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
authors.forename: Saranya
authors.initials: S
authors.lastname: Suriyanarayanan
authors.affiliation: Swiss Hepato-Pancreato-Biliary Center, Department of Visceral and Transplantation Surgery, University Hospital, Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Sonda
authors.affiliation: Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Zurich, Switzerland.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Zuellig
authors.affiliation: Institute for Clinical Chemistry, University Hospital Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Hornemann
authors.affiliation: Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland. Electronic address: larao@access.uzh.ch.
authors.forename: Omolara O
authors.initials: OO
authors.lastname: Ogunshola
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D008559:Memantine / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013107:Sphingolipids / Q000633:toxicity*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000633:toxicity; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C000626286:1-deoxysphingolipid; D000076122:Disks Large Homolog 4 Protein; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D013107:Sphingolipids; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D020830:rac1 GTP-Binding Protein; D013110:Sphingosine; C005682:safingol; D005998:Glycine; D008559:Memantine
keywords: Cytoskeleton; Hereditary sensory and autosomal neuropathy type 1; Lipid metabolism; NMDA receptor; Rac1