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

Authors: Di Pardo, Alba; Amico, Enrico; Basit, Abdul; Armirotti, Andrea; Joshi, Piyush; Neely, M Diana; Vuono, Romina; Castaldo, Salvatore; Digilio, Anna F; Scalabrì, Francesco; Pepe, Giuseppe; Elifani, Francesca; Madonna, Michele; Jeong, Se Kyoo; Park, Bu-Mahn; D'Esposito, Maurizio; Bowman, Aaron B; Barker, Roger A; Maglione, Vittorio

Published In Sci Rep, (2017 07 13)

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.

PubMed ID: 28706199 Exiting the NIEHS site

MeSH Terms: Aged; Aldehyde-Lyases/antagonists & inhibitors; Animals; Disease Models, Animal*; Enzyme Inhibitors/pharmacology*; Gene Expression Regulation/drug effects*; Humans; Huntington Disease/drug therapy*; Huntington Disease/metabolism; Huntington Disease/pathology; Lysophospholipids/metabolism*; Male; Mice; Molecular Targeted Therapy*; Phosphotransferases (Alcohol Group Acceptor)/chemistry; Phosphotransferases (Alcohol Group Acceptor)/metabolism; Receptors, Lysosphingolipid/antagonists & inhibitors; Sphingosine/analogs & derivatives*; Sphingosine/metabolism

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