Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington’s Disease Pre-clinical Model

Abstract

Although several agents have been identified to provide therapeutic benefits in Huntington disease (HD), the number of conventionally used treatments remains limited and only symptomatic. Thus, it is plausible that the need to identify new therapeutic targets for the development of alternative and more effective treatments is becoming increasingly urgent. Recently, the sphingosine-1-phosphate (S1P) axis has been reported to be a valid potential novel molecular target for therapy development in HD. Modulation of aberrant metabolism of S1P in HD has been proved to exert neuroprotective action in vitro settings including human HD iPSC-derived neurons. In this study, we investigated whether promoting S1P production by stimulating Sphingosine Kinase 1 (SPHK1) by the selective activator, K6PC-5, may have therapeutic benefit in vivo in R6/2 HD mouse model. Our findings indicate that chronic administration of 0.05 mg/kg K6PC-5 exerted an overall beneficial effect in R6/2 mice. It significantly slowed down the progressive motor deficit associated with disease progression, modulated S1P metabolism, evoked the activation of pro-survival pathways and markedly reduced the toxic mutant huntingtin (mHtt) aggregation. These results suggest that K6PC-5 may represent a future therapeutic option in HD and may potentially counteract the perturbed brain function induced by deregulated S1P pathways.

Mitochondrial Respiration Changes in R6/2 Huntington’s Disease Model Mice during Aging in a Brain Region Specific Manner

“…Our R6/2 mice displayed pronounced HD-related symptoms at 10–11 weeks of age, as reported previously [ 29 , 30 , 31 ]. These symptoms included motor dysfunction, as assessed by Rotarod, horizontal ladder task and limb clasping tests, reduced brain and body weight gain, and aggregated mHtt in the striatum.…”

“…Therefore, we cannot exclude oxygen or substrate limitations that may have had an impact on respiration in vivo but are masked in our ex vivo approach. In particular, our recent results on the efficiency of promoting sphingosine-1-phosphate (S1P) in the same R6/2 model [ 30 ] highlight the possibility of problems of oxygen availabilities in the R6/2 model and in HD. S1P has been shown to modulate hypoxia signaling by activating hypoxia inducible factor 1 (HIF-1) [ 32 , 33 , 34 ], thus, possibly exerting beneficial effects in HD disease progression via activating protective hypoxia-related pathways.…”

The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease

“…Power analysis has been conducted to determine adequate number of mice to measure motor signs and animal behavioral in a statistically significant manner as previously described 53,54 . Software G Power for sample size calculation has been also used 55 .…”

S1P/S1P Receptor Signaling in Neuromuscolar Disorders

“…Some S1P analogues have been approved for the treatment of multiple sclerosis or have passed phase III trial [31,38], while the effects of other enzyme activators and inhibitors and S1PR agonists/antagonists are being tested in animal models of neurodegenerative diseases. For example, an activator of SphK1 and an agonist S1PR5 exert beneficial effects on a mouse model of Huntington's disease [39,40].…”