LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany.
Institute of Physiology, University Bonn, 53111 Bonn, Germany.
Cells. 2020 Sep 28;9(10):2189. doi: 10.3390/cells9102189.
We have shown that sphingosine 1-phosphate (S1P) generated by sphingosine kinase 2 (SK2) is toxic in neurons lacking S1P-lyase (SGPL1), the enzyme that catalyzes its irreversible cleavage. Interestingly, patients harboring mutations in the gene encoding this enzyme () often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1) confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy, known to be essential for brain health. We now investigated in SGPL1-deficient murine brains two other factors involved in neurodegenerative processes, namely tau phosphorylation and histone acetylation. In hippocampal and cortical slices SGPL1 deficiency and hence S1P accumulation are accompanied by hyperphosphorylation of tau and an elevated acetylation of histone3 (H3) and histone4 (H4). Calcium chelation with BAPTA-AM rescued both tau hyperphosphorylation and histone acetylation, designating calcium as an essential mediator of these (patho)physiological functions of S1P in the brain. Studies in primary cultured neurons and astrocytes derived from SGPL1 mice revealed hyperphosphorylated tau only in SGPL1-deficient neurons and increased histone acetylation only in SGPL1-deficient astrocytes. Both could be reversed to control values with BAPTA-AM, indicating the close interdependence of S1P metabolism, calcium homeostasis, and brain health.
我们已经表明，在缺乏 S1P 裂解酶（SGPL1）的神经元中，由鞘氨醇激酶 2（SK2）产生的鞘氨醇 1-磷酸（S1P）是有毒的，SGPL1 是催化其不可逆裂解的酶。有趣的是，编码该酶的基因突变的患者（）经常表现出神经病理学。在发育性神经特异性缺失 SGPL1 的小鼠模型中进行的研究（SGPL1）证实了 S1P 代谢对突触前结构和神经元自噬的重要性，已知这对大脑健康至关重要。我们现在在 SGPL1 缺陷型鼠脑中研究了另外两个涉及神经退行性过程的因素，即 tau 磷酸化和组蛋白乙酰化。在海马和皮质切片中，SGPL1 缺乏和因此 S1P 积累伴随着 tau 的过度磷酸化和组蛋白 3（H3）和组蛋白 4（H4）的乙酰化升高。BAPTA-AM 的钙螯合挽救了 tau 的过度磷酸化和组蛋白的乙酰化，这表明钙是 S1P 在大脑中发挥这些（病理）生理功能的必需介质。来自 SGPL1 小鼠的原代培养神经元和星形胶质细胞的研究表明，只有在 SGPL1 缺陷型神经元中才存在过度磷酸化的 tau，只有在 SGPL1 缺陷型星形胶质细胞中才存在组蛋白乙酰化增加。两者都可以用 BAPTA-AM 逆转至对照值，表明 S1P 代谢、钙稳态和大脑健康之间密切相互依赖。
