{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T11:18:21Z","timestamp":1777288701661,"version":"3.51.4"},"reference-count":89,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Impuls Forschung, Verbund Norddeutscher Universit\u00e4ten","award":["O.V. and A.U.B."],"award-info":[{"award-number":["O.V. and A.U.B."]}]},{"name":"Impuls Forschung, Verbund Norddeutscher Universit\u00e4ten","award":["A.U.B. and M.J.F."],"award-info":[{"award-number":["A.U.B. and M.J.F."]}]},{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["03Z22JN12 to SC"],"award-info":[{"award-number":["03Z22JN12 to SC"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann\u2013Pick type C1 (NPC1) is a lysosomal storage disorder, inherited as an autosomal-recessive trait. Mutations in the Npc1 gene result in malfunction of the NPC1 protein, leading to an accumulation of unesterified cholesterol and glycosphingolipids. Beside visceral symptoms like hepatosplenomegaly, severe neurological symptoms such as ataxia occur. Here, we analyzed the sphingosine-1-phosphate (S1P)\/S1P receptor (S1PR) axis in different brain regions of Npc1\u2212\/\u2212 mice and evaluated specific effects of treatment with 2-hydroxypropyl-\u03b2-cyclodextrin (HP\u03b2CD) together with the iminosugar miglustat. Using high-performance thin-layer chromatography (HPTLC), mass spectrometry, quantitative real-time PCR (qRT-PCR) and western blot analyses, we studied lipid metabolism in an NPC1 mouse model and human skin fibroblasts. Lipid analyses showed disrupted S1P metabolism in Npc1\u2212\/\u2212 mice in all brain regions, together with distinct changes in S1pr3\/S1PR3 and S1pr5\/S1PR5 expression. Brains of Npc1\u2212\/\u2212 mice showed only weak treatment effects. However, side effects of the treatment were observed in Npc1+\/+ mice. The S1P\/S1PR axis seems to be involved in NPC1 pathology, showing only weak treatment effects in mouse brain. S1pr expression appears to be affected in human fibroblasts, induced pluripotent stem cells (iPSCs)-derived neural progenitor and neuronal differentiated cells. Nevertheless, treatment-induced side effects make examination of further treatment strategies indispensable.<\/jats:p>","DOI":"10.3390\/ijms21124502","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T10:54:59Z","timestamp":1592996099000},"page":"4502","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism"],"prefix":"10.3390","volume":"21","author":[{"given":"Anne","family":"Gl\u00e4ser","sequence":"first","affiliation":[{"name":"Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany"},{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Franziska","family":"Hammerl","sequence":"additional","affiliation":[{"name":"Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6650-7849","authenticated-orcid":false,"given":"Markus H.","family":"Gr\u00e4ler","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, Center for Sepsis Control and Care (CSCC), Center for Molecular Biomedicine (CMB), Jena University Hospital, 07745 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sina M.","family":"Coldewey","sequence":"additional","affiliation":[{"name":"Department of Anaesthesiology and Intensive Care Medicine, Septomics Research Center, Center for Sepsis Control and Care, Jena University Hospital, 07747 Jena, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christin","family":"V\u00f6lkner","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht Kossel\u201d, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2421-8779","authenticated-orcid":false,"given":"Moritz J.","family":"Frech","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht Kossel\u201d, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht Kossel\u201d, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiankai","family":"Luo","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht Kossel\u201d, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), Rostock University Medical Center, University of Rostock, 18147 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"T\u00f6nnies","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6265-9156","authenticated-orcid":false,"given":"Oliver","family":"von Bohlen und Halbach","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Cell Biology, University Medicine Greifswald, 17487 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Brandt","sequence":"additional","affiliation":[{"name":"Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Heimes","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna-Maria","family":"Ne\u00dflauer","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georg Christoph","family":"Korenke","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Klinikum Oldenburg, 26133 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Owczarek-Lipska","sequence":"additional","affiliation":[{"name":"Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany"},{"name":"Junior Research Group, Genetics of childhood brain malformations, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Neidhardt","sequence":"additional","affiliation":[{"name":"Human Genetics, School of Medicine and Health Sciences, University of Oldenburg, 26129 Oldenburg, Germany"},{"name":"Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arndt","family":"Rolfs","sequence":"additional","affiliation":[{"name":"Centogene AG, D-18055 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Wree","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4538-877X","authenticated-orcid":false,"given":"Martin","family":"Witt","sequence":"additional","affiliation":[{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3651-1470","authenticated-orcid":false,"given":"Anja Ursula","family":"Br\u00e4uer","sequence":"additional","affiliation":[{"name":"Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, 26129 Oldenburg, Germany"},{"name":"Institute of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany"},{"name":"Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg,26129 Oldenburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.ymgme.2005.07.007","article-title":"Niemann-Pick C disease: Use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families","volume":"86","author":"Millat","year":"2005","journal-title":"Mol. Genet. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-5-16","article-title":"Niemann-Pick disease type C","volume":"5","author":"Vanier","year":"2010","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.bbalip.2004.08.006","article-title":"The NPC1 protein: Structure implies function","volume":"1685","author":"Scott","year":"2004","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cca.2013.11.026","article-title":"NPC1, intracellular cholesterol trafficking and atherosclerosis","volume":"429","author":"Yu","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S41","DOI":"10.1016\/S0929-693X(10)70010-5","article-title":"Niemann-Pick C disease: History, current research topics, biological and molecular diagnosis","volume":"17","author":"Vanier","year":"2010","journal-title":"Arch. Pediatr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1111\/j.1600-0854.2010.01032.x","article-title":"Lipids on trial: The search for the offending metabolite in Niemann-Pick type C disease","volume":"11","author":"Platt","year":"2010","journal-title":"Traffic"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1126\/science.277.5323.228","article-title":"Niemann-Pick C1 disease gene: Homology to mediators of cholesterol homeostasis","volume":"277","author":"Carstea","year":"1997","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/ajmg.a.31735","article-title":"The National Niemann-Pick C1 disease database: Report of clinical features and health problems","volume":"143a","author":"Garver","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/ajmg.a.32642","article-title":"The clinical spectrum of fetal Niemann-Pick type C","volume":"149a","author":"Spiegel","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1034\/j.1399-0004.2003.00147.x","article-title":"Niemann-Pick disease type C","volume":"64","author":"Vanier","year":"2003","journal-title":"Clin. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/cne.10522","article-title":"Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease","volume":"456","author":"Sarna","year":"2003","journal-title":"J. Comp. Neurol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1002\/jnr.23509","article-title":"Reduced cerebellar neurodegeneration after combined therapy with cyclodextrin\/allopregnanolone and miglustat in NPC1: A mouse model of Niemann-Pick type C1 disease","volume":"93","author":"Maass","year":"2015","journal-title":"J. Neurosci. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1097\/00005072-198805000-00008","article-title":"Cerebellar involvement in murine sphingomyelinosis: A new model of Niemann-Pick disease","volume":"47","author":"Tanaka","year":"1988","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/BF00690966","article-title":"Niemann-Pick disease type C. Study on the nature of the cerebral storage process","volume":"66","author":"Elleder","year":"1985","journal-title":"Acta Neuropathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1186\/1750-1172-8-12","article-title":"Disease and patient characteristics in NP-C patients: Findings from an international disease registry","volume":"8","author":"Patterson","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"108","DOI":"10.3389\/fneur.2017.00108","article-title":"Adult-Onset Niemann-Pick Disease Type C: Rapid Treatment Initiation Advised but Early Diagnosis Remains Difficult","volume":"8","author":"Piroth","year":"2017","journal-title":"Front. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Feng, X., Cozma, C., Pantoom, S., Hund, C., Iwanov, K., Petters, J., Volkner, C., Bauer, C., Vogel, F., and Bauer, P. (2019). Detrmination of the Pathological Features of NPC1 Variants in a Cellular Complementation Teste. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20205185"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Bountouvi, E., Papadopoulou, A., Vanier, M.T., Nyktari, G., Kanellakis, S., Michelakakis, H., and Dinopoulos, A. (2017). Novel NPC1 mutations with different segregation in two related Greek patients with Niemann-Pick type C disease: Molecular study in the extended pedigree and clinical correlations. BMC Med. Genet., 18.","DOI":"10.1186\/s12881-017-0409-4"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13023-014-0140-6","article-title":"Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: A surprisingly stable diagnostic rate spanning almost 40 years","volume":"9","author":"Jahnova","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1002\/humu.10255","article-title":"Identification of 58 novel mutations in Niemann-Pick disease type C: Correlation with biochemical phenotype and importance of PTC1-like domains in NPC1","volume":"22","author":"Park","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1321","DOI":"10.1086\/302626","article-title":"Niemann-Pick C1 disease: The I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype","volume":"65","author":"Millat","year":"1999","journal-title":"Am. J. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"8229","DOI":"10.1074\/jbc.M708735200","article-title":"Niemann-Pick type C1 I1061T mutant encodes a functional protein that is selected for endoplasmic reticulum-associated degradation due to protein misfolding","volume":"283","author":"Gelsthorpe","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/S1474-4422(07)70194-1","article-title":"Miglustat for treatment of Niemann-Pick C disease: A randomised controlled study","volume":"6","author":"Patterson","year":"2007","journal-title":"Lancet Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1080\/00498250601094543","article-title":"The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat","volume":"37","author":"Treiber","year":"2007","journal-title":"Xenobiotica"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1186\/s13023-018-0844-0","article-title":"Miglustat in Niemann-Pick disease type C patients: A review","volume":"13","author":"Pineda","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8362","DOI":"10.1016\/S0021-9258(17)37202-2","article-title":"N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis","volume":"269","author":"Platt","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/S0960-9822(01)00396-7","article-title":"Critical role for glycosphingolipids in Niemann-Pick disease type C","volume":"11","author":"Zervas","year":"2001","journal-title":"Curr. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1111\/j.1651-2227.2008.00656.x","article-title":"Substrate reduction therapy","volume":"97","author":"Platt","year":"2008","journal-title":"Acta Paediatr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1194\/jlr.M000257","article-title":"Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid","volume":"51","author":"Liu","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Davidson, C.D., Ali, N.F., Micsenyi, M.C., Stephney, G., Renault, S., Dobrenis, K., Ory, D.S., Vanier, M.T., and Walkley, S.U. (2009). Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006951"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.ymgme.2012.11.005","article-title":"Effects of cyclodextrin in two patients with Niemann-Pick Type C disease","volume":"108","author":"Matsuo","year":"2013","journal-title":"Mol. Genet. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1203\/PDR.0b013e3181ee4dd2","article-title":"Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life","volume":"68","author":"Ramirez","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Crumling, M.A., Liu, L., Thomas, P.V., Benson, J., Kanicki, A., Kabara, L., Halsey, K., Dolan, D., and Duncan, R.K. (2012). Hearing loss and hair cell death in mice given the cholesterol-chelating agent hydroxypropyl-beta-cyclodextrin. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0053280"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Br\u00e4uer, A.U., Kuhla, A., Holzmann, C., Wree, A., and Witt, M. (2019). Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann-Pick Disease Type C1. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20184392"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fnint.2018.00035","article-title":"Olfactory Performance as an Indicator for Protective Treatment Effects in an Animal Model of Neurodegeneration","volume":"12","author":"Meyer","year":"2018","journal-title":"Front. Integr. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Ebner, L., Gl\u00e4ser, A., Br\u00e4uer, A., Witt, M., Wree, A., Rolfs, A., Frank, M., Vollmar, B., and Kuhla, A. (2018). Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann-Pick-Disease Type C1. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040972"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.neuroscience.2013.08.001","article-title":"Combined therapy with cyclodextrin\/allopregnanolone and miglustat improves motor but not cognitive functions in Niemann-Pick Type C1 mice","volume":"252","author":"Hovakimyan","year":"2013","journal-title":"Neuroscience"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/BF00227765","article-title":"Cerebellar degeneration in the Niemann-Pick type C mouse","volume":"85","author":"Higashi","year":"1993","journal-title":"Acta Neuropathol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/0005-2760(80)90116-2","article-title":"A lysosomal storage disorder in mice characterized by a dual deficiency of sphingomyelinase and glucocerebrosidase","volume":"619","author":"Pentchev","year":"1980","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12944-019-1088-2","article-title":"A therapy with miglustat, 2-hydroxypropyl-\u03b2-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1","volume":"18","author":"Engelmann","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Meyer, A., Wree, A., Gunther, R., Holzmann, C., Schmitt, O., Rolfs, A., and Witt, M. (2017). Increased Regenerative Capacity of the Olfactory Epithelium in Niemann-Pick Disease Type C1. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040777"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1038\/nm.1876","article-title":"Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium","volume":"14","author":"Morgan","year":"2008","journal-title":"Nat. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1182\/blood-2013-03-488692","article-title":"Altered distribution and function of natural killer cells in murine and human Niemann-Pick disease type C1","volume":"123","author":"Speak","year":"2014","journal-title":"Blood"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1038\/nri2974","article-title":"The outs and the ins of sphingosine-1-phosphate in immunity","volume":"11","author":"Spiegel","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/S1388-1981(02)00139-7","article-title":"Signaling of sphingosine-1-phosphate via the S1P\/EDG-family of G-protein-coupled receptors","volume":"1582","author":"Kluk","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2800","DOI":"10.1194\/jlr.M040618","article-title":"Identification of Niemann-Pick C1 disease biomarkers through sphingolipid profiling","volume":"54","author":"Fan","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1042\/BJ20050236","article-title":"NPC1 late endosomes contain elevated levels of non-esterified (\u2018free\u2019) fatty acids and an abnormally glycosylated form of the NPC2 protein","volume":"390","author":"Chen","year":"2005","journal-title":"Biochem. J."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1111\/j.1471-4159.1985.tb04044.x","article-title":"Neurological mutation characterized by dysmyelination in NCTR-Balb\/C mouse with lysosomal lipid storage disease","volume":"45","author":"Weintraub","year":"1985","journal-title":"J. Neurochem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/BF00599187","article-title":"Hypoplasia of the corpus callosum in Niemann-Pick type C disease","volume":"36","author":"Palmeri","year":"1994","journal-title":"Neuroradiology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1186\/s12974-017-0882-x","article-title":"Sphingosine 1-phosphate receptor 3 and RhoA signaling mediate inflammatory gene expression in astrocytes","volume":"14","author":"Dusaban","year":"2017","journal-title":"J. Neuroinflamm."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/S0306-4522(01)00517-6","article-title":"Neurodegeneration in the Niemann-Pick C mouse: Glial involvement","volume":"109","author":"German","year":"2002","journal-title":"Neuroscience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"79","DOI":"10.5483\/BMBRep.2018.51.2.168","article-title":"The role of Purkinje cell-derived VEGF in cerebellar astrogliosis in Niemann-Pick type C mice","volume":"51","author":"Park","year":"2018","journal-title":"BMB Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1523\/JNEUROSCI.4645-04.2005","article-title":"Edg8\/S1P5: An oligodendroglial receptor with dual function on process retraction and cell survival","volume":"25","author":"Jaillard","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1503","DOI":"10.1096\/fj.06-7420com","article-title":"Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration","volume":"21","author":"Novgorodov","year":"2007","journal-title":"Faseb J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1016\/S0140-6736(68)92510-5","article-title":"Sphingolopids and phospholipids of myelin in multiple sclerosis","volume":"2","author":"Cumings","year":"1968","journal-title":"Lancet"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1159\/000362988","article-title":"Sphingolipids: Important players in multiple sclerosis","volume":"34","author":"Halmer","year":"2014","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"170069","DOI":"10.1098\/rsob.170069","article-title":"Sphingolipids: Membrane microdomains in brain development, function and neurological diseases","volume":"7","author":"Olsen","year":"2017","journal-title":"Open Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.bbamem.2017.03.008","article-title":"Sphingosine 1-phosphate\u2014A double edged sword in the brain","volume":"1859","author":"Karunakaran","year":"2017","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Newton, J., Palladino, E.N.D., Weigel, C., Maceyka, M., Gr\u00e4ler, M.H., Senkal, C.E., Enriz, R.D., Marvanova, P., Jampilek, J., and Lima, S. (2020). Targeting defective sphingosine kinase 1 in Niemann-Pick type C disease with an activator mitigates cholesterol accumulation. J. Biol. Chem.","DOI":"10.1074\/jbc.RA120.012659"},{"key":"ref_60","first-page":"149","article-title":"Sphingosine-1 phosphate and central nervous system","volume":"378","author":"Martin","year":"2014","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Fischer, I., Alliod, C., Martinier, N., Newcombe, J., Brana, C., and Pouly, S. (2011). Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0023905"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1111\/j.1750-3639.2008.00182.x","article-title":"FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: Expression of central nervous system genes and reversal of blood-brain-barrier damage","volume":"19","author":"Foster","year":"2009","journal-title":"Brain Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1006\/abio.1999.4157","article-title":"Enzymatic measurement of sphingosine 1-phosphate","volume":"272","author":"Edsall","year":"1999","journal-title":"Anal. Biochem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1093\/hmg\/ddn126","article-title":"Sphingosine kinase 1\/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease","volume":"17","author":"Wu","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1758","DOI":"10.1016\/S0140-6736(17)31465-4","article-title":"Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: A non-randomised, open-label, phase 1-2 trial","volume":"390","author":"Ory","year":"2017","journal-title":"Lancet"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.ymgme.2009.12.006","article-title":"Miglustat in adult and juvenile patients with Niemann-Pick disease type C: Long-term data from a clinical trial","volume":"99","author":"Wraith","year":"2010","journal-title":"Mol. Genet. Metab."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1126\/science.1176709","article-title":"Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate","volume":"325","author":"Hait","year":"2009","journal-title":"Science"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1038\/nn.3728","article-title":"Active, phosphorylated fingolimod inhibits histone deacetylases and facilitates fear extinction memory","volume":"17","author":"Hait","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1096\/fj.201601041R","article-title":"FTY720\/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts","volume":"31","author":"Newton","year":"2017","journal-title":"Faseb J."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","author":"Bligh","year":"1959","journal-title":"Can. J. Biochem. Physiol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/chromsci\/42.1.1","article-title":"Solutions and challenges in sample preparation for chromatography","volume":"42","author":"Moldoveanu","year":"2004","journal-title":"J. Chromatogr. Sci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/S0021-9673(00)99173-8","article-title":"Quantitative densitometric thin-layer chromatography of lipids using copper acetate reagent","volume":"43","author":"Fewster","year":"1969","journal-title":"J. Chromatogr."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s12154-008-0007-1","article-title":"Copper (II) sulfate charring for high sensitivity on-plate fluorescent detection of lipids and sterols: Quantitative analyses of the composition of functional secretory vesicles","volume":"1","author":"Churchward","year":"2008","journal-title":"J. Chem. Biol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-61779-800-9_3","article-title":"Quantification of sphingosine-1-phosphate and related sphingolipids by liquid chromatography coupled to tandem mass spectrometry","volume":"874","author":"Bode","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1007\/s00441-015-2268-7","article-title":"Transcription factor Yin-Yang 2 alters neuronal outgrowth in vitro","volume":"362","author":"Klar","year":"2015","journal-title":"Cell Tissue Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/jnr.490350513","article-title":"Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination","volume":"35","author":"Brewer","year":"1993","journal-title":"J. Neurosci. Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1038\/nprot.2007.149","article-title":"Isolation and culture of rat and mouse oligodendrocyte precursor cells","volume":"2","author":"Chen","year":"2007","journal-title":"Nat. Protoc."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1002\/dvdy.23","article-title":"LPA1, LPA2, LPA4, and LPA6 receptor expression during mouse brain development","volume":"248","author":"Suckau","year":"2019","journal-title":"Dev. Dyn."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1007\/s004399900059","article-title":"NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C","volume":"105","author":"Yamamoto","year":"1999","journal-title":"Hum. Genet."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1002\/0471142727.mb2803s71","article-title":"Establishment and culture of human skin fibroblasts","volume":"71","author":"Villegas","year":"2005","journal-title":"Curr. Protoc. Mol. Biol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/mt.2011.7","article-title":"Gene therapeutic approach using mutation-adapted U1 snRNA to correct a RPGR splice defect in patient-derived cells","volume":"19","author":"Glaus","year":"2011","journal-title":"Mol. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.dib.2017.03.042","article-title":"Dataset in support of the generation of Niemann-Pick disease Type C1 patient-specific iPS cell lines carrying the novel NPC1 mutation c.1180T>C or the prevalent c.3182T>C mutation\u2014Analysis of pluripotency and neuronal differentiation","volume":"12","author":"Peter","year":"2017","journal-title":"Data Brief."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1186\/1750-1172-8-144","article-title":"Niemann-Pick type C1 patient-specific induced pluripotent stem cells display disease specific hallmarks","volume":"8","author":"Trilck","year":"2013","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Kennedy, B.E., LeBlanc, V.G., Mailman, T.M., Fice, D., Burton, I., Karakach, T.K., and Karten, B. (2013). Pre-symptomatic activation of antioxidant responses and alterations in glucose and pyruvate metabolism in Niemann-Pick Type C1-deficient murine brain. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082685"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Maulik, M., Thinakaran, G., and Kar, S. (2013). Alterations in gene expression in mutant amyloid precursor protein transgenic mice lacking Niemann-Pick type C1 protein. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054605"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/8904_2011_49","article-title":"Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking","volume":"2","author":"Zampieri","year":"2012","journal-title":"JIMD Rep."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Velmans, T., Battefeld, A., Geist, B., Farres, A.S., Strauss, U., and Br\u00e4uer, A.U. (2013). Plasticity-related gene 3 promotes neurite shaft protrusion. BMC Neurosci., 14.","DOI":"10.1186\/1471-2202-14-36"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"8116","DOI":"10.1523\/JNEUROSCI.5319-11.2012","article-title":"Aromatase inhibition abolishes LTP generation in female but not in male mice","volume":"32","author":"Vierk","year":"2012","journal-title":"J. Neurosci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4502\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:42:31Z","timestamp":1760175751000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/12\/4502"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,24]]},"references-count":89,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["ijms21124502"],"URL":"https:\/\/doi.org\/10.3390\/ijms21124502","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,24]]}}}