Alam, Shah: Effect of neural ablation of sphingosine-1-phosphate lyase (SGPL1) in glial cells. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Shah Alam}},
title = {Effect of neural ablation of sphingosine-1-phosphate lyase (SGPL1) in glial cells},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
note = {Sphingosine-1-phosphate (S1P) is an evolutionarily conserved catabolic intermediate of sphingolipid metabolism that regulates diverse biological processes in the brain, including neural development, differentiation, and survival. S1P-lyase (SGPL1) irreversibly cleaves S1P in the final step of sphingolipid catabolism. Interestingly, patients harboring mutations in the gene encoding this enzyme (SGPL1) often present with neurological pathologies (Choi and Saba 2019). In this study a mouse model (SGPL1fl/fl/Nes, neural-specific SGPL1-deleted mice) in which SGPL1 was explicitly inactivated in neural cells was used to investigate the impact of SGPL1-deficiency in the brain. Previous studies in this mouse model have confirmed the importance of S1P metabolism for the presynaptic architecture and neuronal autophagy (Mitroi, Deutschmann et al. 2016, Mitroi, Karunakaran et al. 2017).
In the current study, further investigations have been done on this mouse model. The results show that SGPL1 ablation causes astrogliosis in SGPL1-deficient murine brain, a condition characterized by increased expression of GFAP and inflammatory cytokines such as IL-6 and TNFα. Expression of P2Y1R (another protein found in reactive astrocytes) was also found to be increased in SGPL1-deficient murine brain. Increased P2Y1R expression was also an indication of increased nucleotides (ATP or ADP) in the extracellular milieu. Intriguingly, the expressions of glycolytic enzymes were found to be increased, which lead to more ATP production in SGPL1-deficient astrocytes. In addition, mTOR-dependent impaired autophagy was observed in SGPL1-deficient astrocytes. However, upon pharmacological inhibition of S1P receptors (S1PR2/4), both glycolytic enzymes and P2Y1R expression were reversed. Besides, inhibition of P2Y1R reversed the GFAP expression and rescued IL-6 but not TNFα expression in the SGPL1-deficient astrocytes.
Furthermore, microglial activation was evidenced as microglial activation marker protein (Iba1) was found to be increased in SGPL1-deficient murine brains. In addition, autophagy, one of the major mechanisms in the brain that keeps inflammation in check, was also impaired in microglia. Indeed, microglial inflammation was accompanied by defective microglial autophagy in SGPL1-deficient mice. Next, S1PR2 was identified as the mediator of both impaired autophagy and proinflammatory effects (Karunakaran, Alam et al. 2019).
Moreover, two other factors involved in neurodegenerative processes, namely tau phosphorylation and histone acetylation, were also investigated in SGPL1-deficient murine brains. In hippocampal and cortical slices, S1P accumulation was accompanied by hyperphosphorylation of tau and an elevated acetylation of histone3 and histone4. 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. Afterward, it was revealed that hyperphosphorylated tau was found only in SGPL1-deficient neurons and increased histone acetylation was present only in SGPL1-deficient astrocytes (Alam, Piazzesi et al. 2020).},

url = {}

Die folgenden Nutzungsbestimmungen sind mit dieser Ressource verbunden: