Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism.
Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism.
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DOI：
10.1038/srep37064
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发表时间：
2016-11-24
影响因子：
4.6
通讯作者：
van Echten-Deckert G
中科院分区：
文献类型：
--
作者：
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
生物活性脂鞘氨醇1-磷酸(S1P)是神经细胞中特别丰富的鞘磷脂的降解产物。我们以前已经证明，神经元S1P的积聚是有毒的，导致内质网应激和细胞内钙的增加。为了阐明S1P的神经元功能，我们建立了脑特异性基因敲除小鼠模型，在该模型中，负责不可逆地切割S1P的酶S1P裂解酶(SPL)被失活。结构性消融脑内SPL(SPLf1/fl/Nes)，而不是后天神经元前脑限制性SPL缺失(SPLf1/fl/CaMK)，导致S1P显著积聚。因此，在SPLfl/fl/nes小鼠的海马神经元中观察到突触前结构的改变，包括突触小泡的数量和密度显著减少，几种突触前蛋白的表达减少，突触的短期可塑性受损。因此，这些小鼠表现出认知缺陷。在分子水平上，检测到泛素-蛋白酶体系统(UPS)的激活，导致去泛素化酶USP14和几种突触前蛋白的表达减少。抑制蛋白酶体活性后，USP14水平、突触前蛋白表达和突触功能恢复。这些发现证实S1P代谢是调节突触结构和可塑性的一个新的参与者。
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/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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影响因子：
7.1
作者：
Couttas TA;Kain N;Daniels B;Lim XY;Shepherd C;Kril J;Pickford R;Li H;Garner B;Don AS
通讯作者：
Don AS
DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1007/978-1-61779-800-9_3
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Bode, Constantin;Graler, Markus H
通讯作者：
Graler, Markus H
影响因子：
4.8
作者：
Hagen-Euteneuer, Nadine;Luetjohann, Dieter;van Echten-Deckert, Gerhild
通讯作者：
van Echten-Deckert, Gerhild