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Defective sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease

There is increasing evidence that links perturbed sphingolipid metabolism to a range of different neurodegenerative conditions including Huntington’s disease ( HD ).

Researchers have consolidated the evidence that sphingolipid metabolism is aberrant in Huntington’s disease and represents a common pathogenic denominator among multiple preclinical models of the disease and in human patients.

Also, researchers have demonstrated for the first time, that expression of S1P-metabolizing enzymes is significantly altered. In particular, they have found that such a defect shows some regional variation in the HD brain, with especially consistent expression profile abnormalities seen between SPGL1 and SPHK1 in the striatal tissues of all HD human samples and animal models.
Up-regulation of SGPL1 was consistently paralleled by down-regulation of SPHK1, which, under physiological conditions, is known to act as a pro-survival kinase in both CNS and peripheral tissues.

The role of SPHK2 in Huntington’s disease, indeed, remains elusive. The significance of the differential expression of SPHK2 between brain tissues from R6/2 mice and YAC128 mice and HD patients is not straightforward, however it may be that SPHK2 has different roles depending on when and where it is expressed or on its subcellular localization.
Recent findings reported a detrimental effect of SPHK2 in different in vitro models of the disease. Thus, researchers have speculated that elevation of its expression in brain tissues from R6/2 mice may be toxic and further contribute to the worsening of the disease in this mouse model.

Alteration in the expression of S1P-metabolizing enzymes may theoretically correlate with a defective availability of the bioactive lipids in Huntington’s disease.
Accordingly, lipidomic analysis revealed a significant decrease in the levels of S1P in both striatum and cortex of manifest R6/2 mice.
The study also has provided the first in vivo evidence of perturbed ceramide homeostasis, whose increased levels have been described to interfere with mitochondrial channel formation, exert pro-apoptotic actions and to be associated with different neurodegenerative conditions.

Where the reduction of S1P content in the brain tissues of R6/2 mice comes from, is currently unclear. However, taking into account the abnormal increase of Sph levels in the striatum along with accumulation of different Cer species in the cortex of these mice and, considering also the increased levels of S1P-degradative enzyme, SGPL1, in both brain regions, disturbed S1P homeostasis may be due to a combination of poor conversion of Cer to S1P, through Sph production and/or to its enhanced degradation.

Importantly, abnormal expression of SGPL1 and higher levels of Cer, already detectable at early stage of disease in R6/2 mice, likely suggest that S1P metabolism is precociously affected in Huntington’s disease.

This finding corroborated the previous evidence demonstrating that perturbations of the sphingolipid metabolism occur early in the disease. Moreover, the absence of defects in the expression of both SPHK1 and 2 proteins in early manifest mice also indicates that such alterations may progress with the worsening of the disease.

Although not investigated how huntington mutation may alter the expression of S1P-metabolizing enzymes, its early occurrence may likely be attributable to gene expression deregulations, as they may take place before disease onset. To this regard, evidence has indicated that SGPL1 gene expression is usually negatively regulated by the micro RNA - miRNA 125b.
Interestingly, expression of miRNA 125b is described being down-regulated in different pre-clinical models of HD including R6/2 mice.
In the light of that, researchers have hypothesized that SGPL1 over-expression may be likely attributable to micro RNA dysregulation. However, the findings have suggested that aberrant enzyme protein content likely depends on altered gene expression.

The findings provide first insights into perturbed S1P metabolism, which does not represent an epiphenomenon connected to the worsening of the disease, but rather a mutation-dependent biological event with a potential pathogenic role in Huntington’s disease.

Pharmacological interventions aimed at modulating S1P metabolism may pave the way for the development of more targeted and effective therapeutic strategies for the treatment of Huntington’s disease.
The results are in line with recent evidence showing the potential beneficial effect of modulation of SPHKs in vitro, and strengthen the previous findings demonstrating a neuroprotective effect of the S1P receptor stimulation in vivo.
Importantly, the beneficial effects of pharmacological modulation of S1P-metabolizing enzymes in HD human iPSC-derived neurons, further support the hypothesis.

In conclusion, is attractive the evidence that sphingolipid metabolism may represent a target for the discovery of novel therapeutic strategies in Huntington’s disease, especially given that drugs working through its related pathways are already in clinical trial for different other pathological conditions. ( Xagena )

Di Pardo A et al, Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease, Scientific Reports 2017