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

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

Publication date: Jan 08, 2019

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.

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Di Pardo, A., Pepe, G., Castaldo, S., Marracino, F., Capocci, L., Amico, E., Madonna, M., Giova, S., Jeong, S.K., Park, B.M., Park, B.D., and , Maglione. Stimulation of Sphingosine Kinase 1 (SPHK1) Is Beneficial in a Huntington’s Disease Pre-clinical Model. 06741. 2019 Front Mol Neurosci (12):

Concepts Keywords
Brain S1P
Deregulated Neuroprotection
Huntingtin Sphingosine kinase
Huntington Chemistry
Metabolism Sphingosine-1-phosphate
Mice Organic compounds
Mutant Branches of biology
Neurons Lipids
Neuroprotective Huntingtin
Phosphate
Progressive
S1P
Sphingosine
Vivo

Semantics

Type Source Name
drug DRUGBANK Phosphate ion
drug DRUGBANK Sphingosine
disease MESH development
disease DOID Huntington disease
disease MESH Huntington disease
gene UNIPROT SPHK1
gene UNIPROT HTT
disease MESH disease progression
pathway BSID Metabolism
gene UNIPROT MBTPS1

Original Article

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