Sphingosine 1-phosphate lyase ablation disrupts presynaptic architecture and function via an ubiquitin- proteasome mediated mechanism

Abstract

The bioactive lipid sphingosine 1-phosphate (S1P) is a degradation product of sphingolipids that are particularly abundant in neurons. We have shown previously that neuronal S1P accumulation is toxic leading to ER-stress and an increase in intracellular calcium. To clarify the neuronal function of S1P, we generated brain-specific knockout mouse models in which S1P-lyase (SPL), the enzyme responsible for irreversible S1P cleavage was inactivated. Constitutive ablation of SPL in the brain (SPLfl/fl/Nes) but not postnatal neuronal forebrain-restricted SPL deletion (SPLfl/fl/CaMK) caused marked accumulation of S1P. Hence, altered presynaptic architecture including a significant decrease in number and density of synaptic vesicles, decreased expression of several presynaptic proteins, and impaired synaptic short term plasticity were observed in hippocampal neurons from SPLfl/fl/Nes mice. Accordingly, these mice displayed cognitive deficits. At the molecular level, an activation of the ubiquitin-proteasome system (UPS) was detected which resulted in a decreased expression of the deubiquitinating enzyme USP14 and several presynaptic proteins. Upon inhibition of proteasomal activity, USP14 levels, expression of presynaptic proteins and synaptic function were restored. These findings identify S1P metabolism as a novel player in modulating synaptic architecture and plasticity.

Neural sphingosine 1‐phosphate accumulation activates microglia and links impaired autophagy and inflammation

“…We have shown earlier that neural‐targeted depletion of SGPL1 causes accumulation of S1P and to a lesser extent of sphingosine in brains, whereas the levels of other sphingolipids including ceramide and sphingomyelin are not affected (Mitroi et al, ). We now assessed the levels of sphingolipids and the expression of SGPL1 in primary cultured microglial cells and astrocytes generated from these mice.…”

SGPL1 (sphingosine phosphate lyase 1) modulates neuronal autophagy via phosphatidylethanolamine production

“…Notably, inhibition of SPHKs neither rescued LC3-I conversion into LC3-II nor reduced APP accumulation. Another possibility that cannot be fully excluded is the role of sphingosine in autophagy, which is also accumulating to a certain extent in SGPL1-deficient neurons 15,26 . Sphingosine has recently been demonstrated to trigger calcium release from acidic stores, 34 that in turn might activate autophagy.…”

“…The detailed mechanism involved in the regulation of autophagy by PE linked via SGPL1 to S1P metabolism is yet to be explored. We recently generated a new mouse model (SGPL1 fl/fl/Nes ) with developmental neural specific ablation of SGPL1 in the brain, which causes a considerable accumulation of S1P and its metabolic precursor sphingosine with no changes in ceramide and sphingomyelin in the brain 15 . Here we report that neural-targeted depletion of SGPL1 causes cognitive deficits and a decrease of brain PE content along with impaired autophagy and a consequent accumulation of neurodegenerative biomarkers in the brains of SGPL1 fl/fl/Nes mice.…”

Extracellular and intracellular sphingosine‐1‐phosphate distinctly regulates exocytosis in chromaffin cells

“…; Mitroi et al . ), which is mediated by exocytosis of neurotransmitter‐containing synaptic vesicles (Sudhof and Rizo ). Consequently, it has been suggested that S1P may regulate the release of neurotransmitters or hormones from hippocampal neurons (Kajimoto et al .…”

“…Sphingosine-1-phosphate (S1P), an essential bioactive sphingolipid concentrated in the brain and involved in many neurological diseases (Edsall and Spiegel 1999;Takabe et al 2008), plays many physiological roles in neurons, such as neuronal development (Mizugishi et al 2005), neurite extension and retraction (Toman et al 2004;Strochlic et al 2008), and neuronal excitability (MacLennan et al 2001;Zhang et al 2006). Notably, S1P may modulate the strength of synaptic transmission (Kanno et al 2010;Mitroi et al 2016), which is mediated by exocytosis of neurotransmittercontaining synaptic vesicles (Sudhof and Rizo 2011). Consequently, it has been suggested that S1P may regulate the release of neurotransmitters or hormones from hippocampal neurons (Kajimoto et al 2007;Riganti et al 2016;Darios et al 2017), zona glomerulosa cells , neuromuscular junctions (Brailoiu et al 2002) and neuroendocrine chromaffin cells (Pan et al 2006;Darios et al 2017).…”