| Autor: |
Alam S; LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany., Piazzesi A; LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany., Abd El Fatah M; LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany., Raucamp M; Institute of Physiology, University Bonn, 53111 Bonn, Germany., van Echten-Deckert G; LIMES Institute for Membrane Biology and Lipid Biochemistry, Kekulé-Institute, University of Bonn, 53121 Bonn, Germany. |
| Abstrakt: |
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 ( SGPL1 ) often present with neurological pathologies. Studies in a mouse model with a developmental neural-specific ablation of SGPL1 (SGPL1 fl/fl/Nes ) 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 fl/fl/Nes 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. |
