title: Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism.
abstract: The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated. Constitutive ablation of SPL in the brain (SPLfl/fl/Nes) but not postnatal neuronal forebrain-restricted SPL deletion (SPLfl/fl/CaMK) caused marked accumulation of S1P. Hence, altered presynaptic architecture including a significant decrease in number and density of synaptic vesicles, decreased expression of several presynaptic proteins, and impaired synaptic short term plasticity were observed in hippocampal neurons from SPLfl/fl/Nesmice. Accordingly, these mice displayed cognitive deficits. At the molecular level, an activation of the ubiquitin-proteasome system (UPS) was detected which resulted in a decreased expression of the deubiquitinating enzyme USP14 and several presynaptic proteins. Upon inhibition of proteasomal activity, USP14 levels, expression of presynaptic proteins and synaptic function were restored. These findings identify S1P metabolism as a novel player in modulating synaptic architecture and plasticity.
authors.affiliation: LIMES Institute, Membrane Biology &Lipid Biochemistry, University of Bonn, Bonn, Germany.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Mitroi
authors.affiliation: Institute of Physiology, University of Bonn, Bonn, Germany.
authors.forename: André U
authors.initials: AU
authors.lastname: Deutschmann
authors.affiliation: Institute of Physiology, University of Bonn, Bonn, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Raucamp
authors.affiliation: LIMES Institute, Membrane Biology &Lipid Biochemistry, University of Bonn, Bonn, Germany.
authors.forename: Indulekha
authors.initials: I
authors.lastname: Karunakaran
authors.affiliation: Department of Neurology, Molecular Cell Biology Unit, University of Bonn, Bonn, Germany.
authors.forename: Konstantine
authors.initials: K
authors.lastname: Glebov
authors.affiliation: Institute of Physiology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hans
authors.affiliation: Department of Neurology, Molecular Cell Biology Unit, University of Bonn, Bonn, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Walter
authors.affiliation: Children's Hospital Oakland Research Institute, University of California, San Francisco, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Saba
authors.affiliation: Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), and the Center for Molecular Biomedicine (CMB), University Hospital Jena, Jena, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gräler
authors.affiliation: German Centre for Neurodegenerative Diseases (DZNE), Bonn, Germany.
authors.forename: Dan
authors.initials: D
authors.lastname: Ehninger
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Elena
authors.initials: E
authors.lastname: Sopova
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.|Institute of Translational Biomedicine, St. Petersburg State University, 199034 St. Petersburg, Russia.
authors.forename: Oleg
authors.initials: O
authors.lastname: Shupliakov
authors.affiliation: Institute of Physiology, University of Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Swandulla
authors.affiliation: LIMES Institute, Membrane Biology &Lipid Biochemistry, University of Bonn, Bonn, Germany.
authors.forename: Gerhild
authors.initials: G
authors.lastname: van Echten-Deckert
mesh_terms: D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000648:ultrastructure; D019706:Excitatory Postsynaptic Potentials; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000648:ultrastructure*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000648:ultrastructure; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase)