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Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism

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 S...

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Autores principales: Mitroi, Daniel N., Deutschmann, André U., Raucamp, Maren, Karunakaran, Indulekha, Glebov, Konstantine, Hans, Michael, Walter, Jochen, Saba, Julie, Gräler, Markus, Ehninger, Dan, Sopova, Elena, Shupliakov, Oleg, Swandulla, Dieter, van Echten-Deckert, Gerhild
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121647/
https://www.ncbi.nlm.nih.gov/pubmed/27883090
http://dx.doi.org/10.1038/srep37064
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author Mitroi, Daniel N.
Deutschmann, André U.
Raucamp, Maren
Karunakaran, Indulekha
Glebov, Konstantine
Hans, Michael
Walter, Jochen
Saba, Julie
Gräler, Markus
Ehninger, Dan
Sopova, Elena
Shupliakov, Oleg
Swandulla, Dieter
van Echten-Deckert, Gerhild
author_facet Mitroi, Daniel N.
Deutschmann, André U.
Raucamp, Maren
Karunakaran, Indulekha
Glebov, Konstantine
Hans, Michael
Walter, Jochen
Saba, Julie
Gräler, Markus
Ehninger, Dan
Sopova, Elena
Shupliakov, Oleg
Swandulla, Dieter
van Echten-Deckert, Gerhild
author_sort Mitroi, Daniel N.
collection PubMed
description 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 (SPL(fl/fl/Nes)) but not postnatal neuronal forebrain-restricted SPL deletion (SPL(fl/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 SPL(fl/fl/Nes) mice. 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.
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spelling pubmed-51216472016-11-28 Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism Mitroi, Daniel N. Deutschmann, André U. Raucamp, Maren Karunakaran, Indulekha Glebov, Konstantine Hans, Michael Walter, Jochen Saba, Julie Gräler, Markus Ehninger, Dan Sopova, Elena Shupliakov, Oleg Swandulla, Dieter van Echten-Deckert, Gerhild Sci Rep Article 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 (SPL(fl/fl/Nes)) but not postnatal neuronal forebrain-restricted SPL deletion (SPL(fl/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 SPL(fl/fl/Nes) mice. 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. Nature Publishing Group 2016-11-24 /pmc/articles/PMC5121647/ /pubmed/27883090 http://dx.doi.org/10.1038/srep37064 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Mitroi, Daniel N.
Deutschmann, André U.
Raucamp, Maren
Karunakaran, Indulekha
Glebov, Konstantine
Hans, Michael
Walter, Jochen
Saba, Julie
Gräler, Markus
Ehninger, Dan
Sopova, Elena
Shupliakov, Oleg
Swandulla, Dieter
van Echten-Deckert, Gerhild
Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title_full Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title_fullStr Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title_full_unstemmed Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title_short Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
title_sort sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121647/
https://www.ncbi.nlm.nih.gov/pubmed/27883090
http://dx.doi.org/10.1038/srep37064
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