B26 Targeting Sphingosine-1-phosphate Metabolism/axis May Be Beneficial In Huntington Disease Models

Abstract

Background Sphingosine-1-phosphate (S1P) is a potent signalling sphingolipid that acts as a high affinity agonist at five known G protein-coupled receptors, S1PR1-S1PR5, and regulates brain cell homeostasis and survival. S1P metabolism is quite complex and involves the action of different enzymes. S1P is synthesised by sphingosine kinase-1 and -2 (SPHK1 and 2) and degraded either by S1P-phosphate (SPP) or by S1P-lyase (SGPL1). Recent evidence indicates that pharmacological modulation of S1P metabolism/axis may represent a promising therapeutic approach for multiple disorders including neurodegenerative diseases. Aims Here, we aim to explore whether S1P metabolism/signalling pathway may have the potential to be molecularly targeted for developing new therapeutic strategies for the treatment of HD. Methods In vitro experiments were performed in mouse striatal-derived cells expressing wild-type (SThdh7/7) or mutant huntingtin (SThdh111/111). In vivo experiments were carried out in symptomatic R6/2 and YAC128 HD mouse models. Results Our findings reveal an overall aberrant expression of S1P metabolising enzymes both in HD cells and mouse brain tissues with increased levels of SGPL1, which might likely correlate with its increased activity and subsequent alteration of S1P bio-availability. Also, we found that targeting specific molecules in S1P/metabolism/axis activates pro-survival pathways in SThdh111/111 cells. Conclusion These results support the hypothesis of an aberrant metabolism of S1P in HD and indicate that the modulation of its signalling pathway may be beneficial. Thus, we believe S1P axis has the potential of providing the possibility to develop new therapeutic interventions for treating HD. This research is supported by Marie Curie International Incoming Fellowship (PIIF-GA-2011–300197) granted to V. M. within the 7th European Community Framework Programme.