LIMES Institute Membrane Biology and Lipid Biochemistry, University of Bonn, Bonn 53121, Germany.
Cell Death Differ. 2011 Aug;18(8):1356-65. doi: 10.1038/cdd.2011.7. Epub 2011 Feb 18.
We have recently reported that the bioactive lipid sphingosine-1-phosphate (S1P), usually signaling proliferation and anti-apoptosis induces neuronal death when generated by sphingosine-kinase2 and when accumulation due to S1P-lyase deficiency occurs. In the present study, we identify the signaling cascade involved in the neurotoxic effect of sphingoid-base phosphates. We demonstrate that the calcium-dependent cysteine protease calpain mediates neurotoxicity by induction of the endoplasmic reticulum stress-specific caspase cascade and activation of cyclin-dependent kinase5 (CDK5). The latter is involved in an abortive reactivation of the cell cycle and also enhances tau phosphorylation. Neuroanatomical studies in the cerebellum document for the first time that indeed neurons with abundant S1P-lyase expression are those, which degenerate first in S1P-lyase-deficient mice. We therefore propose that an impaired metabolism of glycosphingolipids, which are prevalent in the central nervous system, might be linked via S1P, their common catabolic intermediate, to neuronal death.
我们最近报道称，生物活性脂质鞘氨醇-1-磷酸（S1P）通常通过鞘氨醇激酶 2 产生并由于 S1P 裂合酶缺乏而积累时，会引发神经元死亡，从而起到促进增殖和抗细胞凋亡的作用。在本研究中，我们确定了鞘氨醇碱基磷酸引起神经毒性作用的信号级联。我们证明钙依赖性半胱氨酸蛋白酶钙蛋白酶通过诱导内质网应激特异性半胱天冬酶级联和激活周期蛋白依赖性激酶 5（CDK5）来介导神经毒性。后者涉及细胞周期的无效再激活，并增强 tau 磷酸化。小脑的神经解剖学研究首次证明，在 S1P 裂合酶缺陷型小鼠中，确实是那些 S1P 裂合酶表达丰富的神经元首先退化。因此，我们提出，在中枢神经系统中普遍存在的糖鞘脂代谢受损可能通过 S1P（它们的共同分解中间产物）与神经元死亡相关。
