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Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease

Di Pardo, A., Amico, E., Basit, A., Armirotti, A., Joshi, P., Neely, D.M., Vuono, R., Castaldo, S., Digilio, A.F., Scalabrì, F., and others. (2017) Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease. Scientific Reports, 7 (5280). ISSN 2045-2322. (doi:10.1038/s41598-017-05709-y) (KAR id:79836)

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http://dx.doi.org/10.1038/s41598-017-05709-y

Abstract

Huntington's disease is characterized by a complex and heterogeneous pathogenic profile. Studies have shown that disturbance in lipid homeostasis may represent a critical determinant in the progression of several neurodegenerative disorders. The recognition of perturbed lipid metabolism is only recently becoming evident in HD. In order to provide more insight into the nature of such a perturbation and into the effect its modulation may have in HD pathology, we investigated the metabolism of Sphingosine-1-phosphate (S1P), one of the most important bioactive lipids, in both animal models and patient samples. Here, we demonstrated that S1P metabolism is significantly disrupted in HD even at early stage of the disease and importantly, we revealed that such a dysfunction represents a common denominator among multiple disease models ranging from cells to humans through mouse models. Interestingly, the in vitro anti-apoptotic and the pro-survival actions seen after modulation of S1P-metabolizing enzymes allows this axis to emerge as a new druggable target and unfolds its promising therapeutic potential for the development of more effective and targeted interventions against this incurable condition.

Item Type: Article
DOI/Identification number: 10.1038/s41598-017-05709-y
Uncontrolled keywords: enzyme inhibitor; lyase; lysophospholipid; phosphotransferase; SGPL1 protein, human; sphingosine; sphingosine 1 phosphate receptor; sphingosine 1-phosphate; sphingosine kinase; sphingosine kinase 2, human, aged; analogs and derivatives; animal; antagonists and inhibitors; chemistry; disease model; drug effect; gene expression regulation; human; Huntington chorea; male; metabolism; molecularly targeted therapy; mouse; pathology, Aged; Aldehyde-Lyases; Animals; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Humans; Huntington Disease; Lysophospholipids; Male; Mice; Molecular Targeted Therapy; Phosphotransferases (Alcohol Group Acceptor); Receptors, Lysosphingolipid; Sphingosine
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Romina Vuono
Date Deposited: 29 Jan 2020 10:31 UTC
Last Modified: 20 Feb 2020 09:59 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/79836 (The current URI for this page, for reference purposes)
Vuono, R.: https://orcid.org/0000-0002-5162-3422
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