Background Among all the complex mechanisms underlying the pathogenesis of Huntington’s disease (HD), perturbation of brain lipids has been hypothesised to play a relevant role.

Sphingosine-1-phosphate (S1P), a potent signalling sphingolipid that regulates a number of processes essential for cellular homeostasis, differentiation, motility and cell viability, may represent one of the major player. S1P metabolism is quite complex and involves the action of different enzymes. Normally, synthesised by sphingosine kinase-1 and −2 (SPHK1 and 2) S1P, is irreversible catabolized by S1P-lyase (SGPL1). Emerging evidence indicates that pharmacological interference aimed at modulating S1P pathways may serve as a promising therapeutic approach for multiple disorders including neurodegenerative diseases.

Aims The main goal of this study was to deeper investigate the metabolism of S1P in multiple HD pre-clinical models, in order to clarify the real contribution of its perturbation and to elucidate the potential of finding any novel conceivable therapeutic target for the treatment of disease.

Methods In vitro experiments were carried out in mouse striatal-derived cells expressing endogenous levels of wild-type (STHdh7/7) or mutant (STHdh111/111) huntingtin, respectively. In vivo experiments were performed on brain tissues from symptomatic R6/2 mice and age-matched wild-type (WT) littermates. Western Blotting was used for determining protein expression levels. Quantitative analysis of sphingolipids for lipidomics was carried out in mouse brain samples using Mass Spectrometry.

Results Our data reveal, for the first time, that expression of S1P metabolising enzymes is significantly aberrant in HD and, that their selective modulation results in a strong neuroprotective action in the disease in vitro model. Also, worth of note is the association found between the perturbed expression of such enzymes and the reduced availability of important bio-active sphingolipids in the brain of R6/2 mice.

Conclusions Collectively, our results support the hypothesis that S1P metabolism may represent a good candidate for the development of new therapeutic strategy for HD in the next future.