Güntert TInstitute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Hänggi PInstitute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Switzerland; Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Switzerland.
Othman AInstitute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
Suriyanarayanan SInstitute for Clinical Chemistry, University Hospital Zurich, Switzerland; Competence Center of Personalized Medicine, University of Zurich/ETH Zurich, Switzerland.
Sonda SSwiss 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 RADivision of Endocrinology, Diabetes and Clinical Nutrition, University Hospital, Zurich, Switzerland.
Hornemann TInstitute 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 OOInstitute 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.
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.