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1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling.
Journal article

1-Deoxysphingolipid-induced neurotoxicity involves N-methyl-d-aspartate receptor signaling.

  • Güntert T Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
  • Hänggi P Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
  • Othman A Institute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
  • Suriyanarayanan S Institute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
  • Sonda S 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.
  • Zuellig RA Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Zurich, Switzerland.
  • Hornemann T 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.
  • Ogunshola OO 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.
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  • 2016-03-27
Published in:
  • 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
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/143455
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