{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:21:18Z","timestamp":1788837678516,"version":"build-2803163510"},"reference-count":123,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,6]],"date-time":"2019-09-06T00:00:00Z","timestamp":1567728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Impuls Forschung, Verbund Norddeutscher Universit\u00e4ten","award":["no number"],"award-info":[{"award-number":["no number"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann\u2013Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we summarize the impact of NPC1 pathology on several organ systems, as revealed in experimental animal models and humans, and give an overview of current available treatment options.<\/jats:p>","DOI":"10.3390\/ijms20184392","type":"journal-article","created":{"date-parts":[[2019,9,9]],"date-time":"2019-09-09T03:14:41Z","timestamp":1567998881000},"page":"4392","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Current Challenges in Understanding the Cellular and Molecular Mechanisms in Niemann\u2013Pick Disease Type C1"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3651-1470","authenticated-orcid":false,"given":"Anja U.","family":"Br\u00e4uer","sequence":"first","affiliation":[{"name":"Research Group Anatomy, School of Medicine and Health Sciences, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany"},{"name":"Research Center for Neurosensory Science, Carl von Ossietzky University Oldenburg, D-26129 Oldenburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Kuhla","sequence":"additional","affiliation":[{"name":"Institute for Experimental Surgery, Rostock University Medical Center, Schillingallee 69a, 18057 Rostock, Germany"},{"name":"Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7977-9093","authenticated-orcid":false,"given":"Carsten","family":"Holzmann","sequence":"additional","affiliation":[{"name":"Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany"},{"name":"Institute of Medical Genetics, Rostock University Medical Center, D-18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Wree","sequence":"additional","affiliation":[{"name":"Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany"},{"name":"Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4538-877X","authenticated-orcid":false,"given":"Martin","family":"Witt","sequence":"additional","affiliation":[{"name":"Center of Transdisciplinary Neuroscience Rostock, D-18147 Rostock, Germany"},{"name":"Institute of Anatomy, Rostock University Medical Center, D-18057 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1126\/science.290.5500.2298","article-title":"Identification of HE1 as the second gene of Niemann-Pick C disease","volume":"290","author":"Naureckiene","year":"2000","journal-title":"Science"},{"key":"ref_2","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":"143","author":"Garver","year":"2007","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1002\/jcb.21200","article-title":"Characterization of liver disease and lipid metabolism in the Niemann-Pick C1 mouse","volume":"101","author":"Garver","year":"2007","journal-title":"J. Cell. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1194\/jlr.P000331","article-title":"The national Niemann-Pick Type C1 disease database: correlation of lipid profiles, mutations, and biochemical phenotypes","volume":"51","author":"Garver","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_5","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_6","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":"149","author":"Spiegel","year":"2009","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_7","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_8","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.cell.2015.02.019","article-title":"Cholesterol transport through lysosome-peroxisome membrane contacts","volume":"161","author":"Chu","year":"2015","journal-title":"Cell"},{"key":"ref_9","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_10","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_11","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_12","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_13","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_14","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1042\/BJ20071340","article-title":"A role for NPC1 and NPC2 in intestinal cholesterol absorption--the hypothesis gutted","volume":"408","author":"Liscum","year":"2007","journal-title":"Biochem. J."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/gim.2015.25","article-title":"High incidence of unrecognized visceral\/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets","volume":"18","author":"Wassif","year":"2016","journal-title":"Genet. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1126\/science.3513311","article-title":"A receptor-mediated pathway for cholesterol homeostasis","volume":"232","author":"Brown","year":"1986","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1194\/jlr.M700125-JLR200","article-title":"Receptor-mediated and bulk-phase endocytosis cause macrophage and cholesterol accumulation in Niemann-Pick C disease","volume":"48","author":"Liu","year":"2007","journal-title":"J. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ceb.2006.06.012","article-title":"Intracellular sterol transport and distribution","volume":"18","author":"Maxfield","year":"2006","journal-title":"Curr. Opin. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1146\/annurev.cellbio.22.010305.104656","article-title":"Cholesterol sensing, trafficking, and esterification","volume":"22","author":"Chang","year":"2006","journal-title":"Annu. Rev. Cell. Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5518","DOI":"10.1016\/j.febslet.2006.06.008","article-title":"Lipid imbalance in the neurological disorder, Niemann-Pick C disease","volume":"580","author":"Vance","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1097\/MOL.0b013e3282f9b563","article-title":"The structure and function of Niemann-Pick C1-like 1 protein","volume":"19","author":"Yu","year":"2008","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_22","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_23","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.bbalip.2004.08.008","article-title":"Intracellular trafficking of Niemann-Pick C proteins 1 and 2: obligate components of subcellular lipid transport","volume":"1685","author":"Liscum","year":"2004","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23525","DOI":"10.1074\/jbc.M703848200","article-title":"Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease","volume":"282","author":"Xu","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31594","DOI":"10.1016\/S0021-9258(19)84073-5","article-title":"Mechanism of cholesterol transfer from the Niemann-Pick type C2 protein to model membranes supports a role in lysosomal cholesterol transport","volume":"281","author":"Cheruku","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1016\/j.febslet.2010.04.047","article-title":"Defective cholesterol trafficking in Niemann-Pick C-deficient cells","volume":"584","author":"Peake","year":"2010","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Reddy, J.V., Ganley, I.G., and Pfeffer, S.R. (2006). Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling. PLoS ONE, 1.","DOI":"10.1371\/journal.pone.0000019"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Abe, K., and Sakai, N. (2017). Patient with Niemann-Pick disease type C: over 20 years\u2019 follow-up. BMJ Case Rep., 2017.","DOI":"10.1136\/bcr-2017-220134"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0022-3476(05)81695-6","article-title":"Niemann-Pick disease type C: diagnosis and outcome in children, with particular reference to liver disease","volume":"123","author":"Kelly","year":"1993","journal-title":"J. Pediatr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1007\/s00431-017-3020-y","article-title":"Niemann-Pick disease type C in the newborn period: a single-center experience","volume":"176","author":"Gumus","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1136\/adc.2005.088013","article-title":"The usefulness of bone marrow aspiration in the diagnosis of Niemann-Pick disease type C in infantile liver disease","volume":"91","author":"Rodrigues","year":"2006","journal-title":"Arch. Dis. Child."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"56ra81","DOI":"10.1126\/scitranslmed.3001417","article-title":"Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease","volume":"2","author":"Porter","year":"2010","journal-title":"Sci. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S569","DOI":"10.1007\/s00415-014-7386-8","article-title":"Genetic and laboratory diagnostic approach in Niemann Pick disease type C","volume":"261","author":"Gissen","year":"2014","journal-title":"J. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.ebiom.2016.01.004","article-title":"Towards a new diagnostic standard for Niemann-Pick C disease","volume":"4","author":"Jiang","year":"2016","journal-title":"EBioMedicine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1016\/j.ymgme.2016.06.004","article-title":"Diagnostic tests for Niemann-Pick disease type C (NP-C): A critical review","volume":"118","author":"Vanier","year":"2016","journal-title":"Mol. Genet. Metab."},{"key":"ref_36","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_37","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_38","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. Suppl."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.ijdevneu.2012.07.002","article-title":"Oxidative stress in Niemann-Pick type C patients: a protective role of N-butyl-deoxynojirimycin therapy","volume":"30","author":"Ribas","year":"2012","journal-title":"Int. J. Dev. Neurosci."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1016\/S0140-6736(17)31631-8","article-title":"A hopeful therapy for Niemann-Pick C diseases","volume":"390","author":"Erickson","year":"2017","journal-title":"Lancet"},{"key":"ref_42","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_43","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_44","doi-asserted-by":"crossref","unstructured":"Ebner, L., Glaser, A., Brauer, 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_45","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_46","doi-asserted-by":"crossref","first-page":"276ra26","DOI":"10.1126\/scitranslmed.3010101","article-title":"Intracisternal cyclodextrin prevents cerebellar dysfunction and Purkinje cell death in feline Niemann-Pick type C1 disease","volume":"7","author":"Vite","year":"2015","journal-title":"Sci. Transl. Med."},{"key":"ref_47","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\u20132 trial","volume":"390","author":"Ory","year":"2017","journal-title":"Lancet"},{"key":"ref_48","unstructured":"ClinicalTrials.gov (2019, September 04). Study of VTS-270 (2-hydroxypropyl-\u03b2-cyclodextrin) to Treat Niemann-Pick Type C1 (NPC1) Disease, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT02534844."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Wadman, M. (2019). Update: Twins who were face of controversial rare disease treatment have died. Science.","DOI":"10.1126\/science.aaw0129"},{"key":"ref_50","unstructured":"Puskas, I. (2019, September 04). HPBCD Treatment for Niemann-Pick C: Mallinckrodt Communicated Results of Clinical Trial. Available online: https:\/\/cyclodextrinnews.com\/2018\/11\/13\/hpbcd-treatment-for-niemann-pick-type-c-performed-no-differently-than-placebo\/."},{"key":"ref_51","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_52","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1002\/acn3.306","article-title":"Efficacy and ototoxicity of different cyclodextrins in Niemann-Pick C disease","volume":"3","author":"Davidson","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_53","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_54","doi-asserted-by":"crossref","first-page":"14470","DOI":"10.1523\/JNEUROSCI.4823-07.2007","article-title":"Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse","volume":"27","author":"Repa","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"6367","DOI":"10.1111\/febs.12505","article-title":"The potential of histone deacetylase inhibitors in Niemann\u2014Pick type C disease","volume":"280","author":"Maceyka","year":"2013","journal-title":"FEBS J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"23842","DOI":"10.1074\/jbc.M111.227645","article-title":"An \u201cexacerbate-reverse\u201d strategy in yeast identifies histone deacetylase inhibition as a correction for cholesterol and sphingolipid transport defects in human Niemann-Pick type C disease","volume":"286","author":"Munkacsi","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5620","DOI":"10.1073\/pnas.1014890108","article-title":"Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann-Pick type C1 mutant human fibroblasts","volume":"108","author":"Pipalia","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"688","DOI":"10.1007\/s13311-013-0217-2","article-title":"Treatment of Niemann--pick type C disease by histone deacetylase inhibitors","volume":"10","author":"Helquist","year":"2013","journal-title":"Neurotherapeutics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1042\/bj20021321","article-title":"Histone deacetylases (HDACs): characterization of the classical HDAC family","volume":"370","author":"Caron","year":"2003","journal-title":"Biochem. J."},{"key":"ref_60","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_61","doi-asserted-by":"crossref","first-page":"e156","DOI":"10.1038\/oncsis.2015.16","article-title":"The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERalpha expression and enhances hormonal therapy for breast cancer","volume":"4","author":"Hait","year":"2015","journal-title":"Oncogenesis"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/nature08710","article-title":"Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology","volume":"463","author":"Kirkegaard","year":"2010","journal-title":"Nature"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1080\/17460441.2019.1588882","article-title":"Animal models for Niemann-Pick type C: implications for drug discovery & development","volume":"14","author":"Fog","year":"2019","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"75","DOI":"10.12688\/wellcomeopenres.11854.1","article-title":"Case report: Ursodeoxycholic acid treatment in Niemann-Pick disease type C; clinical experience in four cases","volume":"2","author":"Evans","year":"2017","journal-title":"Wellcome Open Res."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Nicoli, E.R., Al Eisa, N., Cluzeau, C.V., Wassif, C.A., Gray, J., Burkert, K.R., Smith, D.A., Morris, L., Cologna, S.M., and Peer, C.J. (2016). Defective cytochrome P450-catalysed drug metabolism in Niemann-Pick type C disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0152007"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1212\/WNL.0000000000002041","article-title":"Acetyl-dl-leucine in Niemann-Pick type C: A case series","volume":"85","author":"Bremova","year":"2015","journal-title":"Neurology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1194\/jlr.M071274","article-title":"AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease","volume":"58","author":"Xie","year":"2017","journal-title":"J. Lipid Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"3079","DOI":"10.1093\/hmg\/ddy212","article-title":"AAV9 intracerebroventricular gene therapy improves lifespan, locomotor function and pathology in a mouse model of Niemann-Pick type C1 disease","volume":"27","author":"Hughes","year":"2018","journal-title":"Hum. Mol. Genet."},{"key":"ref_69","first-page":"52","article-title":"Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1","volume":"26","author":"Chandler","year":"2017","journal-title":"Hum. Mol. Genet."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Schlegel, V., Thieme, M., Holzmann, C., Witt, M., Grittner, U., Rolfs, A., and Wree, A. (2016). Pharmacologic treatment assigned for Niemann Pick type C1 disease partly changes behavioral traits in wild-type mice. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17111866"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.nbd.2014.03.001","article-title":"Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice","volume":"67","author":"Williams","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1097\/AUD.0b013e3182a362b8","article-title":"Auditory phenotype of Niemann-Pick disease, type C1","volume":"35","author":"King","year":"2014","journal-title":"Ear. Hear."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1007\/s10162-014-0459-7","article-title":"Hearing loss is an early consequence of Npc1 gene deletion in the mouse model of Niemann-Pick disease, type C","volume":"15","author":"King","year":"2014","journal-title":"J. Assoc. Re. Otolaryngol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1203\/PDR.0b013e3181df4623","article-title":"2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease","volume":"68","author":"Ward","year":"2010","journal-title":"Pediatr. Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"21973","DOI":"10.1038\/srep21973","article-title":"Susceptibility of outer hair cells to cholesterol chelator 2-hydroxypropyl-beta-cyclodextrine is prestin-dependent","volume":"6","author":"Takahashi","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1016\/j.jns.2014.12.005","article-title":"Electrophysiological characterization of adult-onset Niemann-Pick type C disease","volume":"348","author":"Iodice","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.mcn.2009.10.007","article-title":"Lack of Niemann-Pick type C1 induces age-related degeneration in the mouse retina","volume":"43","author":"Claudepierre","year":"2010","journal-title":"Mol. Cell. Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Yan, X., Ma, L., Hovakimyan, M., Lukas, J., Wree, A., Frank, M., Guthoff, R., Rolfs, A., Witt, M., and Luo, J. (2014). Defects in the retina of Niemann-pick type C 1 mutant mice. BMC Neurosci., 15.","DOI":"10.1186\/s12868-014-0126-2"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1186\/s13023-015-0348-0","article-title":"Visual evoked potentials of Niemann-Pick type C1 mice reveal an impairment of the visual pathway that is rescued by 2-hydroxypropyl-ss-cyclodextrin","volume":"10","author":"Palladino","year":"2015","journal-title":"Orphanet. J. Rare Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1212\/01.wnl.0000345040.01917.9d","article-title":"Saccades in adult Niemann-Pick disease type C reflect frontal, brainstem, and biochemical deficits","volume":"72","author":"Abel","year":"2009","journal-title":"Neurology"},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Hovakimyan, M., Meyer, A., Lukas, J., Luo, J., Gudziol, V., Hummel, T., Rolfs, A., Wree, A., and Witt, M. (2013). Olfactory deficits in Niemann-Pick type C1 (NPC1) disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0082216"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.1016\/j.bbadis.2014.08.005","article-title":"Excessive microglial activation aggravates olfactory dysfunction by impeding the survival of newborn neurons in the olfactory bulb of Niemann-Pick disease type C1 mice","volume":"1842","author":"Seo","year":"2014","journal-title":"Biochim. Biophys. Acta."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Meyer, A., Wree, A., G\u00fcnther, 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_84","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1097\/NEN.0b013e318286587f","article-title":"Electrodiagnostic testing and histopathologic changes confirm peripheral nervous system myelin abnormalities in the feline model of niemann-pick disease type C","volume":"72","author":"Bagel","year":"2013","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_85","first-page":"263","article-title":"Neuropathological changes in the peripheral nervous system and spinal cord in a transgenic mouse model of Niemann-Pick disease type A","volume":"28","author":"Marmiroli","year":"2009","journal-title":"Clin. Neuropathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1007\/BF03195698","article-title":"Expression of Npc1 in glial cells corrects sterility in Npc1(\u2212\/\u2212) mice","volume":"50","author":"Donohue","year":"2009","journal-title":"J. Appl. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1210\/me.2003-0323","article-title":"Aberrant intracellular cholesterol transport disrupts pituitary and ovarian function","volume":"18","author":"Gevry","year":"2004","journal-title":"Molecul. Endocrinol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1095\/biolreprod.114.119412","article-title":"Dysregulation of testicular cholesterol metabolism following spontaneous mutation of the niemann-pick c1 gene in mice","volume":"91","author":"Akpovi","year":"2014","journal-title":"Biol. Reprod."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1210\/endo.133.6.8243319","article-title":"The murine Niemann-Pick type C lesion affects testosterone production","volume":"133","author":"Roff","year":"1993","journal-title":"Endocrinology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1002\/mrd.20559","article-title":"Sperm defects in mice lacking a functional Niemann-Pick C1 protein","volume":"73","author":"Fan","year":"2006","journal-title":"Mol. Reprod. Dev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0065-1281(85)80054-4","article-title":"Adrenal changes in Niemann-Pick disease: Differences between sphingomyelinase deficiency and type C","volume":"76","author":"Elleder","year":"1985","journal-title":"Acta. Histochemica."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2994","DOI":"10.1002\/jnr.22126","article-title":"Amelioration of enteric neuropathology in a mouse model of Niemann-Pick C by Npc1 expression in enteric glia","volume":"87","author":"Kapur","year":"2009","journal-title":"J. Neurosci. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1007\/s10620-018-4914-x","article-title":"Gastrointestinal tract pathology in a BALB\/c Niemann-Pick disease type C1 null mouse model","volume":"63","author":"Cougnoux","year":"2018","journal-title":"Dig. Dis. Sci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1007\/s10620-018-4953-3","article-title":"Crohn\u2019s disease in Niemann-Pick disease type C1: Caught in the cross-Fire of host-microbial interactions","volume":"63","author":"Cavounidis","year":"2018","journal-title":"Dig. Dis. Sci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1136\/gutjnl-2015-310382","article-title":"Impaired antibacterial autophagy links granulomatous intestinal inflammation in Niemann-Pick disease type C1 and XIAP deficiency with NOD2 variants in Crohn\u2019s disease","volume":"66","author":"Schwerd","year":"2017","journal-title":"Gut"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1177\/003693300505000213","article-title":"Niemann-pick disease type C and Crohn\u2019s disease","volume":"50","author":"Steven","year":"2005","journal-title":"Scott. Med. J."},{"key":"ref_97","first-page":"143","article-title":"The effect of lysosomal storage diseases on secretory cells: An ultrastructural study of pancreas as an example","volume":"27","author":"Hammel","year":"1995","journal-title":"J. Submicrosc. Cytol. Pathol."},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Staretz-Chacham, O., Aviram, M., Morag, I., Goldbart, A., and Hershkovitz, E. (2018). Pulmonary involvement in Niemann-Pick C type 1. Eur. J. Pediatr.","DOI":"10.1007\/s00431-018-3219-6"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Roszell, B.R., Tao, J.Q., Yu, K.J., Gao, L., Huang, S., Ning, Y., Feinstein, S.I., Vite, C.H., and Bates, S.R. (2013). Pulmonary abnormalities in animal models due to Niemann-Pick type C1 (NPC1) or C2 (NPC2) disease. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0067084"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/s13353-018-0431-z","article-title":"A pilot study of direct delivery of hydroxypropyl-beta-cyclodextrin to the lung by the nasal route in a mouse model of Niemann-Pick C1 disease: motor performance is unaltered and lung disease is worsened","volume":"59","author":"Erickson","year":"2018","journal-title":"J. Appl. Genet."},{"key":"ref_101","first-page":"13","article-title":"Respiratory impairment in Niemann-Pick B disease: Two case reports and review for the pulmonologist","volume":"76","author":"Capron","year":"2019","journal-title":"Respir. Med. Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/S0344-0338(97)80025-8","article-title":"Pathology of visceral organs and bone marrow in an acid sphingomyelinase deficient knock-out mouse line, mimicking human Niemann-Pick disease type A. A light and electron microscopic study","volume":"193","author":"Kuemmel","year":"1997","journal-title":"Pathol. Res. Pract."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/jps.2600830615","article-title":"Parenteral hydroxypropyl cyclodextrins: intravenous and intracerebral administration of lipophiles","volume":"83","author":"Pitha","year":"1994","journal-title":"J. Pharm. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1177\/000992289403301010","article-title":"Severe failure to thrive and liver dysfunction as the main manifestations of a new variant of Niemann-Pick disease","volume":"33","author":"Reif","year":"1994","journal-title":"Clin. Pediatr. (Phila)"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1097\/00004836-199209000-00013","article-title":"Liver failure and the sea-blue histiocyte\/adult Niemann-Pick disease. Case report and review of the literature","volume":"15","author":"Putterman","year":"1992","journal-title":"J. Clin. Gastroenterol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3109\/15513818909022387","article-title":"Progressive neonatal liver failure due to type C Niemann-Pick isease","volume":"9","author":"Rutledge","year":"1989","journal-title":"Pediatr. Pathol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1007\/BF01621810","article-title":"Fetal Niemann-Pick disease type C: ultrastructural and lipid findings in liver and spleen","volume":"422","author":"Dumontel","year":"1993","journal-title":"Virchows Arch. A Pathol. Anat. Histopathol."},{"key":"ref_108","first-page":"44","article-title":"Niemann-pick disease type C in neonatal cholestasis at a North American Center","volume":"35","author":"Yerushalmi","year":"2002","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1002\/hep.20868","article-title":"Cholesterol accumulation and liver cell death in mice with Niemann-Pick type C disease","volume":"42","author":"Beltroy","year":"2005","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1194\/jlr.M800415-JLR200","article-title":"TNF-(alpha) plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease","volume":"50","author":"Rimkunas","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"2372","DOI":"10.1194\/jlr.M007211","article-title":"Recovery from liver disease in a Niemann-Pick type C mouse model","volume":"51","author":"Sayre","year":"2010","journal-title":"J. Lipid Res."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.gene.2013.05.080","article-title":"The C57BL\/6J Niemann-Pick C1 mouse model with decreased gene dosage has impaired glucose tolerance independent of body weight","volume":"527","author":"Jelinek","year":"2013","journal-title":"Gene"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2161","DOI":"10.1194\/jlr.R400010-JLR200","article-title":"PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis","volume":"45","author":"Li","year":"2004","journal-title":"J. Lipid Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1248\/bpb.b14-00726","article-title":"Efficacy of 2-hydroxypropyl-beta-cyclodextrin in Niemann-Pick disease type C model mice and its pharmacokinetic analysis in a patient with the disease","volume":"38","author":"Tanaka","year":"2015","journal-title":"Biol. Pharm. Bull."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.imlet.2017.07.004","article-title":"Overview of immune abnormalities in lysosomal storage disorders","volume":"188","author":"Rigante","year":"2017","journal-title":"Immunol. Lett."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12944-019-1088-2","article-title":"A therapy with miglustat, 2-hydroxypropyl-ss-cyclodextrin and allopregnanolone restores splenic cholesterol homeostasis in Niemann-pick disease type C1","volume":"18","author":"Nesslauer","year":"2019","journal-title":"Lipids Health Dis."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.atherosclerosis.2010.11.020","article-title":"Detection of coronary atherosclerotic plaques with superficial proteoglycans and foam cells using real-time intrinsic fluorescence spectroscopy","volume":"215","author":"Angheloiu","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1172\/JCI115747","article-title":"Lipoprotein lipase is synthesized by macrophage-derived foam cells in human coronary atherosclerotic plaques","volume":"89","author":"Gordon","year":"1992","journal-title":"J. Clin. Invest."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1097\/MOL.0000000000000279","article-title":"So much cholesterol: the unrecognized importance of smooth muscle cells in atherosclerotic foam cell formation","volume":"27","author":"Dubland","year":"2016","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"185","DOI":"10.3389\/fphys.2016.00185","article-title":"Beta-cyclodextrins decrease cholesterol release and ABC-associated transporter expression in smooth muscle cells and aortic endothelial cells","volume":"7","author":"Coisne","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.vph.2015.04.008","article-title":"Treatment with KLEPTOSE(R) CRYSMEB reduces mouse atherogenesis by impacting on lipid profile and Th1 lymphocyte response","volume":"72","author":"Montecucco","year":"2015","journal-title":"Vascul. Pharmacol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"333ra50","DOI":"10.1126\/scitranslmed.aad6100","article-title":"Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming","volume":"8","author":"Zimmer","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_123","first-page":"571098","article-title":"Changes in caries risk and activity of a 9-year-old patient with niemann-pick disease type C","volume":"2015","author":"Freitas","year":"2015","journal-title":"Case Rep. Dent."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4392\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:17:19Z","timestamp":1760188639000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/18\/4392"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,6]]},"references-count":123,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2019,9]]}},"alternative-id":["ijms20184392"],"URL":"https:\/\/doi.org\/10.3390\/ijms20184392","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,6]]}}}