Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy.
Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy.
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DOI：
10.1038/srep15213
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发表时间：
2015-10-19
影响因子：
4.6
通讯作者：
Tsvetkov AS
中科院分区：
文献类型：
--
作者：
Moruno Manchon JF;Uzor NE;Dabaghian Y;Furr-Stimming EE;Finkbeiner S;Tsvetkov AS
自噬是一种重要的体内平衡机制，它消除了长寿命蛋白质、蛋白质聚集体和受损的细胞器。它的失调涉及许多神经退行性疾病。因此，自噬是一个有前途的目标，钝化神经变性。我们在原代神经元中寻找新的自噬途径，并确定了胞质鞘氨醇-1-磷酸（S1 P）途径作为神经元自噬的调节因子。S1 P是一种由鞘氨醇激酶1（SK 1）在细胞质中产生的生物活性脂质，与细胞存活有关。我们发现SK 1通过自噬增强通量，而S1 P代谢酶降低该通量。当自噬受到刺激时，SK 1重新定位到神经元的内体/自噬体。SK 1的显性负性形式的表达抑制自噬体合成。在亨廷顿病的神经元模型中，抑制S1 P-裂解酶可保护神经元免受突变亨廷顿蛋白诱导的神经毒性。这些结果确定了S1 P通路作为神经元自噬的一种新的调节因子，并为神经退行性疾病的治疗提供了一个新的靶点。
Autophagy is an important homeostatic mechanism that eliminates long-lived proteins, protein aggregates and damaged organelles. Its dysregulation is involved in many neurodegenerative disorders. Autophagy is therefore a promising target for blunting neurodegeneration. We searched for novel autophagic pathways in primary neurons and identified the cytosolic sphingosine-1-phosphate (S1P) pathway as a regulator of neuronal autophagy. S1P, a bioactive lipid generated by sphingosine kinase 1 (SK1) in the cytoplasm, is implicated in cell survival. We found that SK1 enhances flux through autophagy and that S1P-metabolizing enzymes decrease this flux. When autophagy is stimulated, SK1 relocalizes to endosomes/autophagosomes in neurons. Expression of a dominant-negative form of SK1 inhibits autophagosome synthesis. In a neuron model of Huntington’s disease, pharmacologically inhibiting S1P-lyase protected neurons from mutant huntingtin-induced neurotoxicity. These results identify the S1P pathway as a novel regulator of neuronal autophagy and provide a new target for developing therapies for neurodegenerative disorders.