Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2017-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-017-05709-y |
| _version_ | 1818681434605355008 |
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| author | Alba Di Pardo Enrico Amico Abdul Basit Andrea Armirotti Piyush Joshi M. Diana 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 |
| author_facet | Alba Di Pardo Enrico Amico Abdul Basit Andrea Armirotti Piyush Joshi M. Diana 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 |
| author_sort | Alba Di Pardo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T10:02:53Z |
| format | Article |
| id | doaj.art-bf0f9516edd7471585e05c6cc1d03c10 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-17T10:02:53Z |
| publishDate | 2017-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-bf0f9516edd7471585e05c6cc1d03c102022-12-21T21:53:15ZengNature PortfolioScientific Reports2045-23222017-07-017111410.1038/s41598-017-05709-yDefective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s diseaseAlba Di Pardo0Enrico Amico1Abdul Basit2Andrea Armirotti3Piyush Joshi4M. Diana Neely5Romina Vuono6Salvatore Castaldo7Anna F. Digilio8Francesco Scalabrì9Giuseppe Pepe10Francesca Elifani11Michele Madonna12Se Kyoo Jeong13Bu-Mahn Park14Maurizio D’Esposito15Aaron B. Bowman16Roger A. Barker17Vittorio Maglione18IRCCS NeuromedIRCCS NeuromedDepartment of Drug Discovery and Development, Fondazione Istituto Italiano di TecnologiaDepartment of Drug Discovery and Development, Fondazione Istituto Italiano di TecnologiaDepartments of Pediatrics, Neurology and Biochemistry, Vanderbilt University (VU) and VU Medical Center Pediatric Neurology Research LabDepartments of Pediatrics, Neurology and Biochemistry, Vanderbilt University (VU) and VU Medical Center Pediatric Neurology Research LabJohn van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of CambridgeIRCCS NeuromedInstitute of Biosciences and Bioresources (IBBR), National Research Council (CNR)IRCCS NeuromedIRCCS NeuromedIRCCS NeuromedIRCCS NeuromedDepartment of of Cosmetic Science, Seowon UniversityNeoPharm USA Inc. Engelwood CliffsIRCCS NeuromedDepartments of Pediatrics, Neurology and Biochemistry, Vanderbilt University (VU) and VU Medical Center Pediatric Neurology Research LabJohn van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of CambridgeIRCCS NeuromedAbstract 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.https://doi.org/10.1038/s41598-017-05709-y |
| spellingShingle | Alba Di Pardo Enrico Amico Abdul Basit Andrea Armirotti Piyush Joshi M. Diana 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 Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease Scientific Reports |
| title | Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease |
| title_full | Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease |
| title_fullStr | Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease |
| title_full_unstemmed | Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease |
| title_short | Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington’s disease |
| title_sort | defective sphingosine 1 phosphate metabolism is a druggable target in huntington s disease |
| url | https://doi.org/10.1038/s41598-017-05709-y |
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