{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:51:28Z","timestamp":1792036288733,"version":"4.4.0"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T00:00:00Z","timestamp":1499904000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,13]],"date-time":"2017-07-13T00:00:00Z","timestamp":1499904000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Huntington\u2019s 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 <jats:italic>in vitro<\/jats:italic> 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.<\/jats:p>","DOI":"10.1038\/s41598-017-05709-y","type":"journal-article","created":{"date-parts":[[2017,7,7]],"date-time":"2017-07-07T09:35:23Z","timestamp":1499420123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["Defective Sphingosine-1-phosphate metabolism is a druggable target in Huntington\u2019s disease"],"prefix":"10.1038","volume":"7","author":[{"given":"Alba","family":"Di Pardo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Amico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1164-5520","authenticated-orcid":false,"given":"Abdul","family":"Basit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Armirotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piyush","family":"Joshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Diana","family":"Neely","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Vuono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Castaldo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna F.","family":"Digilio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Scalabr\u00ec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pepe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Elifani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Madonna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Se Kyoo","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bu-Mahn","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurizio","family":"D\u2019Esposito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron B.","family":"Bowman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger A.","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vittorio","family":"Maglione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,7,13]]},"reference":[{"key":"5709_CR1","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/B978-0-12-381328-2.00013-4","volume":"98","author":"MJ Novak","year":"2011","unstructured":"Novak, M. J. & Tabrizi, S. J. Huntington\u2019s disease: clinical presentation and treatment. Int Rev Neurobiol 98, 297\u2013323, doi:10.1016\/B978-0-12-381328-2.00013-4 (2011).","journal-title":"Int Rev Neurobiol"},{"key":"5709_CR2","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1016\/j.neuron.2016.02.003","volume":"89","author":"F Saudou","year":"2016","unstructured":"Saudou, F. & Humbert, S. The Biology of Huntingtin. Neuron 89, 910\u2013926, doi:10.1016\/j.neuron.2016.02.003 (2016).","journal-title":"Neuron"},{"key":"5709_CR3","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1042\/BJ20071619","volume":"412","author":"S Imarisio","year":"2008","unstructured":"Imarisio, S. et al. Huntington\u2019s disease: from pathology and genetics to potential therapies. Biochem J 412, 191\u2013209, doi:10.1042\/BJ20071619 (2008).","journal-title":"Biochem J"},{"key":"5709_CR4","doi-asserted-by":"publisher","first-page":"4072","DOI":"10.1523\/JNEUROSCI.6348-09.2010","volume":"30","author":"V Maglione","year":"2010","unstructured":"Maglione, V. et al. Impaired ganglioside metabolism in Huntington\u2019s disease and neuroprotective role of GM1. J Neurosci 30, 4072\u20134080, doi:10.1523\/JNEUROSCI.6348-09.2010 (2010).","journal-title":"J Neurosci"},{"key":"5709_CR5","doi-asserted-by":"publisher","first-page":"9932","DOI":"10.1523\/JNEUROSCI.3355-05.2005","volume":"25","author":"M Valenza","year":"2005","unstructured":"Valenza, M. et al. Dysfunction of the cholesterol biosynthetic pathway in Huntington\u2019s disease. J Neurosci 25, 9932\u20139939, doi:10.1523\/JNEUROSCI.3355-05.2005 (2005).","journal-title":"J Neurosci"},{"key":"5709_CR6","doi-asserted-by":"publisher","first-page":"e0134465","DOI":"10.1371\/journal.pone.0134465","volume":"10","author":"JB Carroll","year":"2015","unstructured":"Carroll, J. B. et al. HdhQ111 Mice Exhibit Tissue Specific Metabolite Profiles that Include Striatal Lipid Accumulation. PLoS One 10, e0134465, doi:10.1371\/journal.pone.0134465 (2015).","journal-title":"PLoS One"},{"key":"5709_CR7","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/j.jacl.2009.11.003","volume":"4","author":"RC Block","year":"2010","unstructured":"Block, R. C., Dorsey, E. R., Beck, C. A., Brenna, J. T. & Shoulson, I. Altered cholesterol and fatty acid metabolism in Huntington disease. J Clin Lipidol 4, 17\u201323, doi:10.1016\/j.jacl.2009.11.003 (2010).","journal-title":"J Clin Lipidol"},{"key":"5709_CR8","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1021\/acs.biochem.5b00900","volume":"55","author":"X Gao","year":"2016","unstructured":"Gao, X. et al. Cholesterol Modifies Huntingtin Binding to, Disruption of, and Aggregation on Lipid Membranes. Biochemistry 55, 92\u2013102, doi:10.1021\/acs.biochem.5b00900 (2016).","journal-title":"Biochemistry"},{"key":"5709_CR9","doi-asserted-by":"publisher","first-page":"457","DOI":"10.3389\/fnins.2016.00457","volume":"10","author":"A Di Pardo","year":"2016","unstructured":"Di Pardo, A., Amico, E. & Maglione, V. Impaired Levels of Gangliosides in the Corpus Callosum of Huntington Disease Animal Models. Front Neurosci 10, 457, doi:10.3389\/fnins.2016.00457 (2016).","journal-title":"Front Neurosci"},{"key":"5709_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/978-1-4419-6741-1_1","volume":"688","author":"CR Gault","year":"2010","unstructured":"Gault, C. R., Obeid, L. M. & Hannun, Y. A. An overview of sphingolipid metabolism: from synthesis to breakdown. Adv Exp Med Biol 688, 1\u201323 (2010).","journal-title":"Adv Exp Med Biol"},{"key":"5709_CR11","doi-asserted-by":"publisher","first-page":"1401","DOI":"10.1042\/BST20140159","volume":"42","author":"FM Goni","year":"2014","unstructured":"Goni, F. M., Sot, J. & Alonso, A. Biophysical properties of sphingosine, ceramides and other simple sphingolipids. Biochem Soc Trans 42, 1401\u20131408, doi:10.1042\/BST20140159 (2014).","journal-title":"Biochem Soc Trans"},{"key":"5709_CR12","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1242\/dev.094805","volume":"141","author":"K Mendelson","year":"2014","unstructured":"Mendelson, K., Evans, T. & Hla, T. Sphingosine 1-phosphate signalling. Development 141, 5\u20139, doi:10.1242\/dev.094805 (2014).","journal-title":"Development"},{"key":"5709_CR13","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrm1103","volume":"4","author":"S Spiegel","year":"2003","unstructured":"Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4, 397\u2013407, doi:10.1038\/nrm1103 (2003).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"5709_CR14","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.tcb.2011.09.003","volume":"22","author":"M Maceyka","year":"2012","unstructured":"Maceyka, M., Harikumar, K. B., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22, 50\u201360, doi:10.1016\/j.tcb.2011.09.003 (2012).","journal-title":"Trends Cell Biol"},{"key":"5709_CR15","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.1172\/JCI76369","volume":"125","author":"RL Proia","year":"2015","unstructured":"Proia, R. L. & Hla, T. Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125, 1379\u20131387, doi:10.1172\/JCI76369 (2015).","journal-title":"J Clin Invest"},{"key":"5709_CR16","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1074\/jbc.R600028200","volume":"282","author":"S Spiegel","year":"2007","unstructured":"Spiegel, S. & Milstien, S. Functions of the multifaceted family of sphingosine kinases and some close relatives. J Biol Chem 282, 2125\u20132129, doi:10.1074\/jbc.R600028200 (2007).","journal-title":"J Biol Chem"},{"key":"5709_CR17","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/S1388-1981(02)00132-4","volume":"1582","author":"H Le Stunff","year":"2002","unstructured":"Le Stunff, H., Peterson, C., Liu, H., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate and lipid phosphohydrolases. Biochim Biophys Acta 1582, 8\u201317 (2002).","journal-title":"Biochim Biophys Acta"},{"key":"5709_CR18","first-page":"5","volume":"85","author":"VI Morozov","year":"2013","unstructured":"Morozov, V. I., Sakuta, G. A. & Kalinski, M. I. Sphingosine-1-phosphate: distribution, metabolism and role in the regulation of cellular functions. Ukr Biokhim Zh (1999) 85, 5\u201321 (2013).","journal-title":"Ukr Biokhim Zh (1999)"},{"key":"5709_CR19","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1096\/fj.10-167502","volume":"25","author":"GM Strub","year":"2011","unstructured":"Strub, G. M. et al. Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration. FASEB J 25, 600\u2013612, doi:10.1096\/fj.10-167502 (2011).","journal-title":"FASEB J"},{"key":"5709_CR20","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1007\/s00395-011-0223-7","volume":"106","author":"L Gomez","year":"2011","unstructured":"Gomez, L. et al. A novel role for mitochondrial sphingosine-1-phosphate produced by sphingosine kinase-2 in PTP-mediated cell survival during cardioprotection. Basic Res Cardiol 106, 1341\u20131353, doi:10.1007\/s00395-011-0223-7 (2011).","journal-title":"Basic Res Cardiol"},{"key":"5709_CR21","doi-asserted-by":"publisher","first-page":"pe1","DOI":"10.1126\/scisignal.3103pe1","volume":"3","author":"A Riccio","year":"2010","unstructured":"Riccio, A. New endogenous regulators of class I histone deacetylases. Sci Signal 3, pe1, doi:10.1126\/scisignal.3103pe1 (2010).","journal-title":"Sci Signal"},{"key":"5709_CR22","doi-asserted-by":"publisher","first-page":"37118","DOI":"10.1074\/jbc.M502207200","volume":"280","author":"M Maceyka","year":"2005","unstructured":"Maceyka, M. et al. SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism. J Biol Chem 280, 37118\u201337129, doi:10.1074\/jbc.M502207200 (2005).","journal-title":"J Biol Chem"},{"key":"5709_CR23","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.advenzreg.2009.10.024","volume":"50","author":"M Serra","year":"2010","unstructured":"Serra, M. & Saba, J. D. Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv Enzyme Regul 50, 349\u2013362, doi:10.1016\/j.advenzreg.2009.10.024 (2010).","journal-title":"Adv Enzyme Regul"},{"key":"5709_CR24","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1016\/j.cellsig.2011.02.009","volume":"23","author":"A Kumar","year":"2011","unstructured":"Kumar, A., Byun, H. S., Bittman, R. & Saba, J. D. The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent manner. Cell Signal 23, 1144\u20131152, doi:10.1016\/j.cellsig.2011.02.009 (2011).","journal-title":"Cell Signal"},{"key":"5709_CR25","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/2051-5960-2-9","volume":"2","author":"TA Couttas","year":"2014","unstructured":"Couttas, T. A. et al. Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer\u2019s disease pathogenesis. Acta Neuropathol Commun 2, 9, doi:10.1186\/2051-5960-2-9 (2014).","journal-title":"Acta Neuropathol Commun"},{"key":"5709_CR26","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/2051-5960-2-12","volume":"2","author":"J Ceccom","year":"2014","unstructured":"Ceccom, J. et al. Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer\u2019s disease. Acta Neuropathol Commun 2, 12, doi:10.1186\/2051-5960-2-12 (2014).","journal-title":"Acta Neuropathol Commun"},{"key":"5709_CR27","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1016\/j.neurobiolaging.2008.05.010","volume":"31","author":"X He","year":"2010","unstructured":"He, X., Huang, Y., Li, B., Gong, C. X. & Schuchman, E. H. Deregulation of sphingolipid metabolism in Alzheimer\u2019s disease. Neurobiol Aging 31, 398\u2013408, doi:10.1016\/j.neurobiolaging.2008.05.010 (2010).","journal-title":"Neurobiol Aging"},{"key":"5709_CR28","doi-asserted-by":"crossref","unstructured":"Sivasubramanian, M., Dheen, S. T. & Tay, S. S. W. Alteration in the sphingolipid metabolism leads to activation of the apoptotic cascade in the MPTP induced mouse model of Parkinson\u2019s disease. Faseb Journal 27 (2013).","DOI":"10.1096\/fasebj.27.1_supplement.533.8"},{"key":"5709_CR29","doi-asserted-by":"publisher","first-page":"e135","DOI":"10.1371\/journal.pgen.0030135","volume":"3","author":"JM Lee","year":"2007","unstructured":"Lee, J. M. et al. Unbiased gene expression analysis implicates the huntingtin polyglutamine tract in extra-mitochondrial energy metabolism. PLoS Genet 3, e135, doi:10.1371\/journal.pgen.0030135 (2007).","journal-title":"PLoS Genet"},{"key":"5709_CR30","doi-asserted-by":"publisher","first-page":"15213","DOI":"10.1038\/srep15213","volume":"5","author":"JF Moruno Manchon","year":"2015","unstructured":"Moruno Manchon, J. F. et al. Cytoplasmic sphingosine-1-phosphate pathway modulates neuronal autophagy. Sci Rep 5, 15213, doi:10.1038\/srep15213 (2015).","journal-title":"Sci Rep"},{"key":"5709_CR31","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1093\/hmg\/ddx046","volume":"26","author":"JF Moruno-Manchon","year":"2017","unstructured":"Moruno-Manchon, J. F. et al. Inhibiting sphingosine kinase 2 mitigates mutant Huntingtin-induced neurodegeneration in neuron models of Huntington disease. Hum Mol Genet 26, 1305\u20131317, doi:10.1093\/hmg\/ddx046 (2017).","journal-title":"Hum Mol Genet"},{"key":"5709_CR32","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1038\/nmeth.3940","volume":"13","author":"L Pirhaji","year":"2016","unstructured":"Pirhaji, L. et al. Revealing disease-associated pathways by network integration of untargeted metabolomics. Nat Methods 13, 770\u2013776, doi:10.1038\/nmeth.3940 (2016).","journal-title":"Nat Methods"},{"key":"5709_CR33","doi-asserted-by":"publisher","first-page":"3528","DOI":"10.1073\/pnas.1114502109","volume":"109","author":"A Di Pardo","year":"2012","unstructured":"Di Pardo, A. et al. Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice. Proc Natl Acad Sci USA 109, 3528\u20133533, doi:10.1073\/pnas.1114502109 (2012).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5709_CR34","doi-asserted-by":"publisher","first-page":"2251","DOI":"10.1093\/hmg\/ddt615","volume":"23","author":"A Di Pardo","year":"2014","unstructured":"Di Pardo, A. et al. FTY720 (fingolimod) is a neuroprotective and disease-modifying agent in cellular and mouse models of Huntington disease. Hum Mol Genet 23, 2251\u20132265, doi:10.1093\/hmg\/ddt615 (2014).","journal-title":"Hum Mol Genet"},{"key":"5709_CR35","doi-asserted-by":"publisher","first-page":"4958","DOI":"10.1093\/hmg\/ddv218","volume":"24","author":"A Miguez","year":"2015","unstructured":"Miguez, A. et al. Fingolimod (FTY720) enhances hippocampal synaptic plasticity and memory in Huntington\u2019s disease by preventing p75NTR up-regulation and astrocyte-mediated inflammation. Hum Mol Genet 24, 4958\u20134970, doi:10.1093\/hmg\/ddv218 (2015).","journal-title":"Hum Mol Genet"},{"key":"5709_CR36","doi-asserted-by":"publisher","first-page":"5767","DOI":"10.1111\/j.1742-4658.2008.06709.x","volume":"275","author":"J Bras","year":"2008","unstructured":"Bras, J., Singleton, A., Cookson, M. R. & Hardy, J. Emerging pathways in genetic Parkinson\u2019s disease: Potential role of ceramide metabolism in Lewy body disease. FEBS J 275, 5767\u20135773, doi:10.1111\/j.1742-4658.2008.06709.x (2008).","journal-title":"FEBS J"},{"key":"5709_CR37","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s00018-012-1038-x","volume":"70","author":"C Mencarelli","year":"2013","unstructured":"Mencarelli, C. & Martinez-Martinez, P. Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70, 181\u2013203, doi:10.1007\/s00018-012-1038-x (2013).","journal-title":"Cell Mol Life Sci"},{"key":"5709_CR38","doi-asserted-by":"publisher","first-page":"537","DOI":"10.3233\/JAD-2011-111202","volume":"29","author":"V Filippov","year":"2012","unstructured":"Filippov, V. et al. Increased ceramide in brains with Alzheimer\u2019s and other neurodegenerative diseases. J Alzheimers Dis 29, 537\u2013547, doi:10.3233\/JAD-2011-111202 (2012).","journal-title":"J Alzheimers Dis"},{"key":"5709_CR39","doi-asserted-by":"publisher","first-page":"346783","DOI":"10.1155\/2015\/346783","volume":"2015","author":"M Jazvinscak Jembrek","year":"2015","unstructured":"Jazvinscak Jembrek, M., Hof, P. R. & Simic, G. Ceramides in Alzheimer\u2019s Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and Abeta Accumulation. Oxid Med Cell Longev 2015, 346783, doi:10.1155\/2015\/346783 (2015).","journal-title":"Oxid Med Cell Longev"},{"key":"5709_CR40","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1097\/00005072-198511000-00003","volume":"44","author":"JP Vonsattel","year":"1985","unstructured":"Vonsattel, J. P. et al. Neuropathological classification of Huntington\u2019s disease. J Neuropathol Exp Neurol 44, 559\u2013577 (1985).","journal-title":"J Neuropathol Exp Neurol"},{"key":"5709_CR41","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/S0092-8674(00)81369-0","volume":"87","author":"L Mangiarini","year":"1996","unstructured":"Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493\u2013506 (1996).","journal-title":"Cell"},{"key":"5709_CR42","doi-asserted-by":"publisher","first-page":"3248","DOI":"10.1523\/JNEUROSCI.19-08-03248.1999","volume":"19","author":"RJ Carter","year":"1999","unstructured":"Carter, R. J. et al. Characterization of progressive motor deficits in mice transgenic for the human Huntington\u2019s disease mutation. J Neurosci 19, 3248\u20133257 (1999).","journal-title":"J Neurosci"},{"key":"5709_CR43","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1093\/hmg\/ddg169","volume":"12","author":"EJ Slow","year":"2003","unstructured":"Slow, E. J. et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet 12, 1555\u20131567 (2003).","journal-title":"Hum Mol Genet"},{"key":"5709_CR44","doi-asserted-by":"publisher","first-page":"5189","DOI":"10.1007\/s00216-015-8585-6","volume":"407","author":"A Basit","year":"2015","unstructured":"Basit, A., Piomelli, D. & Armirotti, A. Rapid evaluation of 25 key sphingolipids and phosphosphingolipids in human plasma by LC-MS\/MS. Anal Bioanal Chem 407, 5189\u20135198, doi:10.1007\/s00216-015-8585-6 (2015).","journal-title":"Anal Bioanal Chem"},{"key":"5709_CR45","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1111\/j.1750-3639.2011.00501.x","volume":"22","author":"S Kim","year":"2012","unstructured":"Kim, S., Steelman, A. J., Zhang, Y., Kinney, H. C. & Li, J. Aberrant upregulation of astroglial ceramide potentiates oligodendrocyte injury. Brain Pathol 22, 41\u201357, doi:10.1111\/j.1750-3639.2011.00501.x (2012).","journal-title":"Brain Pathol"},{"key":"5709_CR46","doi-asserted-by":"publisher","first-page":"e0150372","DOI":"10.1371\/journal.pone.0150372","volume":"11","author":"AM Tidball","year":"2016","unstructured":"Tidball, A. M. et al. Genomic Instability Associated with p53 Knockdown in the Generation of Huntington\u2019s Disease Human Induced Pluripotent Stem Cells. PLoS One 11, e0150372, doi:10.1371\/journal.pone.0150372 (2016).","journal-title":"PLoS One"},{"key":"5709_CR47","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1038\/nbt.1529","volume":"27","author":"SM Chambers","year":"2009","unstructured":"Chambers, S. M. et al. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat Biotechnol 27, 275\u2013280, doi:10.1038\/nbt.1529 (2009).","journal-title":"Nat Biotechnol"},{"key":"5709_CR48","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1021\/cn300029t","volume":"3","author":"MD Neely","year":"2012","unstructured":"Neely, M. D. et al. DMH1, a highly selective small molecule BMP inhibitor promotes neurogenesis of hiPSCs: comparison of PAX6 and SOX1 expression during neural induction. ACS Chem Neurosci 3, 482\u2013491, doi:10.1021\/cn300029t (2012).","journal-title":"ACS Chem Neurosci"},{"key":"5709_CR49","doi-asserted-by":"publisher","first-page":"054124","DOI":"10.1063\/1.4934713","volume":"9","author":"JA Brown","year":"2015","unstructured":"Brown, J. A. et al. Recreating blood-brain barrier physiology and structure on chip: A novel neurovascular microfluidic bioreactor. Biomicrofluidics 9, 054124, doi:10.1063\/1.4934713 (2015).","journal-title":"Biomicrofluidics"},{"key":"5709_CR50","doi-asserted-by":"publisher","first-page":"1836","DOI":"10.1038\/nprot.2012.116","volume":"7","author":"Y Shi","year":"2012","unstructured":"Shi, Y., Kirwan, P. & Livesey, F. J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7, 1836\u20131846, doi:10.1038\/nprot.2012.116 (2012).","journal-title":"Nat Protoc"},{"key":"5709_CR51","doi-asserted-by":"publisher","first-page":"6850","DOI":"10.1523\/JNEUROSCI.6467-10.2011","volume":"31","author":"N Takasugi","year":"2011","unstructured":"Takasugi, N. et al. BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci 31, 6850\u20136857, doi:10.1523\/JNEUROSCI.6467-10.2011 (2011).","journal-title":"J Neurosci"},{"key":"5709_CR52","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.16370","author":"D Hatoum","year":"2017","unstructured":"Hatoum, D., Haddadi, N., Lin, Y., Nassif, N. T. & McGowan, E. M. Mammalian sphingosine kinase (SphK) isoenzymes and isoform expression: challenges for SphK as an oncotarget. Oncotarget. doi:10.18632\/oncotarget.16370 (2017).","journal-title":"Oncotarget"},{"key":"5709_CR53","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1042\/BJ20060251","volume":"397","author":"K Venkataraman","year":"2006","unstructured":"Venkataraman, K. et al. Extracellular export of sphingosine kinase-1a contributes to the vascular S1P gradient. Biochem J 397, 461\u2013471, doi:10.1042\/BJ20060251 (2006).","journal-title":"Biochem J"},{"key":"5709_CR54","doi-asserted-by":"publisher","first-page":"3531","DOI":"10.1182\/blood-2009-10-243444","volume":"115","author":"A Weigert","year":"2010","unstructured":"Weigert, A. et al. Cleavage of sphingosine kinase 2 by caspase-1 provokes its release from apoptotic cells. Blood 115, 3531\u20133540, doi:10.1182\/blood-2009-10-243444 (2010).","journal-title":"Blood"},{"key":"5709_CR55","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1158\/1541-7786.MCR-08-0156","volume":"7","author":"SE Schnitzer","year":"2009","unstructured":"Schnitzer, S. E., Weigert, A., Zhou, J. & Brune, B. Hypoxia enhances sphingosine kinase 2 activity and provokes sphingosine-1-phosphate-mediated chemoresistance in A549 lung cancer cells. Mol Cancer Res 7, 393\u2013401, doi:10.1158\/1541-7786.MCR-08-0156 (2009).","journal-title":"Mol Cancer Res"},{"key":"5709_CR56","doi-asserted-by":"publisher","first-page":"9128","DOI":"10.1074\/jbc.M111.302380","volume":"287","author":"N Hagen-Euteneuer","year":"2012","unstructured":"Hagen-Euteneuer, N., Lutjohann, D., Park, H., Merrill, A. H. Jr. & van Echten-Deckert, G. Sphingosine 1-phosphate (S1P) lyase deficiency increases sphingolipid formation via recycling at the expense of de novo biosynthesis in neurons. J Biol Chem 287, 9128\u20139136, doi:10.1074\/jbc.M111.302380 (2012).","journal-title":"J Biol Chem"},{"key":"5709_CR57","doi-asserted-by":"publisher","first-page":"e16571","DOI":"10.1371\/journal.pone.0016571","volume":"6","author":"EV Berdyshev","year":"2011","unstructured":"Berdyshev, E. V. et al. Intracellular S1P generation is essential for S1P-induced motility of human lung endothelial cells: role of sphingosine kinase 1 and S1P lyase. PLoS One 6, e16571, doi:10.1371\/journal.pone.0016571 (2011).","journal-title":"PLoS One"},{"key":"5709_CR58","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1242\/dmm.013631","volume":"7","author":"DH Nguyen-Tran","year":"2014","unstructured":"Nguyen-Tran, D. H. et al. Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy. Dis Model Mech 7, 41\u201354, doi:10.1242\/dmm.013631 (2014).","journal-title":"Dis Model Mech"},{"key":"5709_CR59","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1007\/s11064-014-1240-3","volume":"39","author":"M Gassowska","year":"2014","unstructured":"Gassowska, M., Cieslik, M., Wilkaniec, A. & Strosznajder, J. B. Sphingosine kinases\/sphingosine-1-phosphate and death Signalling in APP-transfected cells. Neurochem Res 39, 645\u2013652, doi:10.1007\/s11064-014-1240-3 (2014).","journal-title":"Neurochem Res"},{"key":"5709_CR60","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1016\/j.bbrc.2015.02.007","volume":"458","author":"F Ji","year":"2015","unstructured":"Ji, F. et al. K6PC-5, a novel sphingosine kinase 1 (SphK1) activator, alleviates dexamethasone-induced damages to osteoblasts through activating SphK1-Akt signaling. Biochem Biophys Res Commun 458, 568\u2013575, doi:10.1016\/j.bbrc.2015.02.007 (2015).","journal-title":"Biochem Biophys Res Commun"},{"key":"5709_CR61","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.1038\/jid.2008.66","volume":"128","author":"JH Hong","year":"2008","unstructured":"Hong, J. H. et al. K6PC-5, a direct activator of sphingosine kinase 1, promotes epidermal differentiation through intracellular Ca2+ signaling. J Invest Dermatol 128, 2166\u20132178, doi:10.1038\/jid.2008.66 (2008).","journal-title":"J Invest Dermatol"},{"key":"5709_CR62","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1089\/dna.2015.2959","volume":"34","author":"JJ Shao","year":"2015","unstructured":"Shao, J. J., Peng, Y., Wang, L. M., Wang, J. K. & Chen, X. Activation of SphK1 by K6PC-5 Inhibits Oxygen-Glucose Deprivation\/Reoxygenation-Induced Myocardial Cell Death. DNA Cell Biol 34, 669\u2013676, doi:10.1089\/dna.2015.2959 (2015).","journal-title":"DNA Cell Biol"},{"key":"5709_CR63","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1083\/jcb.200203123","volume":"158","author":"H Le Stunff","year":"2002","unstructured":"Le Stunff, H., Galve-Roperh, I., Peterson, C., Milstien, S. & Spiegel, S. Sphingosine-1-phosphate phosphohydrolase in regulation of sphingolipid metabolism and apoptosis. J Cell Biol 158, 1039\u20131049, doi:10.1083\/jcb.200203123 (2002).","journal-title":"J Cell Biol"},{"key":"5709_CR64","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1016\/j.neuroscience.2010.10.021","volume":"171","author":"T Kanno","year":"2010","unstructured":"Kanno, T. et al. Regulation of synaptic strength by sphingosine 1-phosphate in the hippocampus. Neuroscience 171, 973\u2013980, doi:10.1016\/j.neuroscience.2010.10.021 (2010).","journal-title":"Neuroscience"},{"key":"5709_CR65","doi-asserted-by":"publisher","unstructured":"Moruno-Manchon, J. F. et al. Inhibiting sphingosine kinase 2 mitigates mutant huntingtin-induced neurodegeneration in neuron models of Huntington disease. Hum Mol Genet, doi:10.1093\/hmg\/ddx046 (2017).","DOI":"10.1093\/hmg\/ddx046"},{"key":"5709_CR66","doi-asserted-by":"publisher","first-page":"924","DOI":"10.3390\/ijms16010924","volume":"16","author":"C Huang","year":"2015","unstructured":"Huang, C. & Freter, C. Lipid metabolism, apoptosis and cancer therapy. Int J Mol Sci 16, 924\u2013949, doi:10.3390\/ijms16010924 (2015).","journal-title":"Int J Mol Sci"},{"key":"5709_CR67","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.bbamem.2014.11.018","volume":"1848","author":"J Stiban","year":"2015","unstructured":"Stiban, J. & Perera, M. Very long chain ceramides interfere with C16-ceramide-induced channel formation: A plausible mechanism for regulating the initiation of intrinsic apoptosis. Biochim Biophys Acta 1848, 561\u2013567, doi:10.1016\/j.bbamem.2014.11.018 (2015).","journal-title":"Biochim Biophys Acta"},{"key":"5709_CR68","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1007\/978-1-4020-8831-5_9","volume":"49","author":"RM Adibhatla","year":"2008","unstructured":"Adibhatla, R. M. & Hatcher, J. F. Altered lipid metabolism in brain injury and disorders. Subcell Biochem 49, 241\u2013268, doi:10.1007\/978-1-4020-8831-5_9 (2008).","journal-title":"Subcell Biochem"},{"key":"5709_CR69","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1007\/s12017-010-8114-x","volume":"12","author":"O Ben-David","year":"2010","unstructured":"Ben-David, O. & Futerman, A. H. The role of the ceramide acyl chain length in neurodegeneration: involvement of ceramide synthases. Neuromolecular Med 12, 341\u2013350, doi:10.1007\/s12017-010-8114-x (2010).","journal-title":"Neuromolecular Med"},{"key":"5709_CR70","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.pneurobio.2007.03.004","volume":"83","author":"JH Cha","year":"2007","unstructured":"Cha, J. H. Transcriptional signatures in Huntington\u2019s disease. Prog Neurobiol 83, 228\u2013248, doi:10.1016\/j.pneurobio.2007.03.004 (2007).","journal-title":"Prog Neurobiol"},{"key":"5709_CR71","doi-asserted-by":"publisher","first-page":"e0166940","DOI":"10.1371\/journal.pone.0166940","volume":"11","author":"W Yang","year":"2016","unstructured":"Yang, W. et al. miR-125b Enhances IL-8 Production in Early-Onset Severe Preeclampsia by Targeting Sphingosine-1-Phosphate Lyase 1. PLoS One 11, e0166940, doi:10.1371\/journal.pone.0166940 (2016).","journal-title":"PLoS One"},{"key":"5709_CR72","doi-asserted-by":"publisher","first-page":"e23837","DOI":"10.1371\/journal.pone.0023837","volume":"6","author":"J Ghose","year":"2011","unstructured":"Ghose, J., Sinha, M., Das, E., Jana, N. R. & Bhattacharyya, N. P. Regulation of miR-146a by RelA\/NFkB and p53 in STHdh(Q111)\/Hdh(Q111) cells, a cell model of Huntington\u2019s disease. PLoS One 6, e23837, doi:10.1371\/journal.pone.0023837 (2011).","journal-title":"PLoS One"},{"key":"5709_CR73","doi-asserted-by":"publisher","first-page":"109","DOI":"10.12703\/P6-109","volume":"6","author":"PJ Gonzalez-Cabrera","year":"2014","unstructured":"Gonzalez-Cabrera, P. J., Brown, S., Studer, S. M. & Rosen, H. S1P signaling: new therapies and opportunities. F1000Prime Rep 6, 109, doi:10.12703\/P6-109 (2014).","journal-title":"F1000Prime Rep"},{"key":"5709_CR74","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.phrs.2016.09.025","volume":"113","author":"WS Chew","year":"2016","unstructured":"Chew, W. S., Wang, W. & Herr, D. R. To fingolimod and beyond: The rich pipeline of drug candidates that target S1P signaling. Pharmacol Res 113, 521\u2013532, doi:10.1016\/j.phrs.2016.09.025 (2016).","journal-title":"Pharmacol Res"}],"updated-by":[{"DOI":"10.1038\/s41598-018-23083-1","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2018,5,24]],"date-time":"2018-05-24T00:00:00Z","timestamp":1527120000000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05709-y","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05709-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05709-y.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T06:36:58Z","timestamp":1671777418000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-05709-y"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,7,13]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["5709"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-05709-y","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-018-23083-1","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,7,13]]},"assertion":[{"value":"3 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 July 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2018","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"5280"}}