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

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

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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.

Original languageEnglish
Article number5280
JournalScientific Reports
Volume7
Issue number1
DOIs
Publication statusPublished - Dec 1 2017

ASJC Scopus subject areas

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    Di Pardo, A., Amico, E., Basit, A., Armirotti, A., Joshi, P., Neely, D. M., Vuono, R., Castaldo, S., Digilio, A. F., Scalabrì, F., Pepe, G., Elifani, F., Madonna, M., Jeong, S. K., Park, B. M., D'Esposito, M., Bowman, A. B., Barker, R. A., & Maglione, V. (2017). Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington's disease. Scientific Reports, 7(1), [5280]. https://doi.org/10.1038/s41598-017-05709-y