The impact of sphingosine-1-phosphate (S1P)-lyase deficiency on astrocyte physiology and on epigenetic regulation

点击翻译按钮获取中文摘要

Sphingosine-1-phosphate (S1P), an evolutionarily conserved catabolic intermediate of sphingolipid metabolism regulates diverse biological processes in the brain including neural development, differentiation, and survival. Another interesting finding is its function in the regulation of histone acetylation. S1P specifically binds to histone deacetylases HDAC1 and HDAC2 thus inhibiting their enzymatic activity and preventing the removal of acetyl groups from lysine residues within histone tails. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism generating ethanolamine phosphate and a long-chain aldehyde. There is no doubt on the essential role of S1P in brain development. Yet, reports on the involvement of S1P in the pathology of neurodegenerative diseases are rather conflicting. In an attempt to clarify the function of S1P in the brain, we generated a mouse model in which SGPL1 was inactivated specifically in neural cells (SGPL1fl/fl/Nes). As expected, SGPL1 ablation leads to S1P accumulation in the brain causing neuronal ER-stress, an increase in intracellular calcium, impairment of presynaptic architecture and function, accompanied by cognitive deficits in mice. In addition, we demonstrated that SGPL1 deficiency blocks neuronal autophagy at its early stages because of reduced phosphatidylethanolamine (PE) production. Thus accumulation of S1P and the simultaneous decline of PE in SGPL1 deficient brains cause considerable neuronal damage. As neuronal damage might induce inflammation, we investigated the microglial alterations as a result of S1P accumulation in neural cells. We evidenced increased microglial activation in the brains of SGPL1fl/fl/Nes mice as shown by morphological as well as biochemical markers. Also, an increased secretion of pro-inflammatory cytokines in FACS-sorted and cultured microglia from SGPL1fl/fl/Nes mice was noticed. Given the increasing number of human neuropathalogies as a result of mutations in the gene encoding SGPL1, we decided to extend our studies and analyse on the one hand the fate of astrocytes in SGPL1fl/fl/Nes mice and on the other hand the epigenetic consequences of S1P accumulation in SGPL1 depleted brains. The present project thus aims to answer two central questions:I) How does neural-targeted ablation of SGPL1 induce astrogliosis?II) Which molecular mechanism underlies S1P dependent regulation of histone acetylation?Specific goals are:Ia. To explore the causes of astrogliosis and of its consequences. Ib. To assess autophagy in primary cultured astrocytes.Ic. To verify our hypothesis regarding the molecular mechanism that links SGPL1 activity, activation of astrocytes and autophagy.IIa. To investigate histone acetylation in SGPL1 deficient brains.IIb: To study the involvement of calcium regarding histone acetylation.Preliminary results strongly encourage implementation of this project.