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Sci Rep. 2017 Jul 13;7(1):5280. doi: 10.1038/s41598-017-05709-y.

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

Author information

1
IRCCS Neuromed, Pozzilli, Italy.
2
Department of Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, Genova, Italy.
3
Departments of Pediatrics, Neurology and Biochemistry, Vanderbilt University (VU) and VU Medical Center Pediatric Neurology Research Lab, Nashville, TN, USA.
4
John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
5
Institute of Biosciences and Bioresources (IBBR), National Research Council (CNR), Naples, Italy.
6
Department of of Cosmetic Science, Seowon University, Cheongju, Korea.
7
NeoPharm USA Inc. Engelwood Cliffs, New Jersey, USA.
8
Institute of Genetics and Biophysics "A. Buzzati-Traverso", Naples, Italy.
9
IRCCS Neuromed, Pozzilli, Italy. vittorio.maglione@neuromed.it.

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.

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