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

Daniel N. Mitroi, André U. Deutschmann, Maren Raucamp, Indulekha Karunakaran, Konstantine Glebov, Michael Hans, Jochen Walter, Julie Saba, Markus Gräler, Dan Ehninger, Elena Sopova, Oleg Shupliakov, Dieter Swandulla, Gerhild Van Echten-Deckert

Research output

11 Citations (Scopus)

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 (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.

Original languageEnglish
Article number37064
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 24 Nov 2016

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Proteasome Endopeptidase Complex
Ubiquitin
Lyases
Neurons
Sphingolipids
Proteins
Neuronal Plasticity
Synaptic Vesicles
Poisons
Brain
Prosencephalon
Knockout Mice
sphingosine 1-phosphate
sphingosine 1-phosphate lyase (aldolase)
Calcium
Lipids
Enzymes

Scopus subject areas

  • General

Cite this

Mitroi, D. N., Deutschmann, A. U., Raucamp, M., Karunakaran, I., Glebov, K., Hans, M., ... Van Echten-Deckert, G. (2016). Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism. Scientific Reports, 6, [37064]. https://doi.org/10.1038/srep37064
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. In: Scientific Reports. 2016 ; Vol. 6.
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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 (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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Mitroi, DN, Deutschmann, AU, Raucamp, M, Karunakaran, I, Glebov, K, Hans, M, Walter, J, Saba, J, Gräler, M, Ehninger, D, Sopova, E, Shupliakov, O, Swandulla, D & Van Echten-Deckert, G 2016, 'Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism', Scientific Reports, vol. 6, 37064. https://doi.org/10.1038/srep37064

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.

In: Scientific Reports, Vol. 6, 37064, 24.11.2016.

Research output

TY - JOUR

T1 - Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism

AU - Mitroi, Daniel N.

AU - Deutschmann, André U.

AU - Raucamp, Maren

AU - Karunakaran, Indulekha

AU - Glebov, Konstantine

AU - Hans, Michael

AU - Walter, Jochen

AU - Saba, Julie

AU - Gräler, Markus

AU - Ehninger, Dan

AU - Sopova, Elena

AU - Shupliakov, Oleg

AU - Swandulla, Dieter

AU - Van Echten-Deckert, Gerhild

PY - 2016/11/24

Y1 - 2016/11/24

N2 - 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.

AB - 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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