{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T18:20:47Z","timestamp":1787509247276,"version":"build-2736575974"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T00:00:00Z","timestamp":1687219200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20K11571"],"award-info":[{"award-number":["20K11571"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21K15892"],"award-info":[{"award-number":["21K15892"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal of Neurochemistry"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Krabbe disease is an inherited demyelinating disease caused by a genetic deficiency of the lysosomal enzyme galactosylceramide (GalCer) \u03b2\u2010galactosidase (GALC). The\n                    <jats:italic>Twitcher<\/jats:italic>\n                    (Twi) mouse is a naturally occurring, genetically and enzymatically authentic mouse model that mimics infantile\u2010onset Krabbe disease. The major substrate for GALC is the myelin lipid GalCer. However, the pathogenesis of Krabbe disease has long been explained by the accumulation of psychosine, a lyso\u2010derivative of GalCer. Two metabolic pathways have been proposed for the accumulation of psychosine: a synthetic pathway in which galactose is transferred to sphingosine and a degradation pathway in which GalCer is deacylated by acid ceramidase (ACDase). Saposin\u2010D (Sap\u2010D) is essential for the degradation of ceramide by ACDase in lysosome. In this study, we generated Twi mice with a Sap\u2010D deficiency (Twi\/Sap\u2010D KO), which are genetically deficient in both GALC and Sap\u2010D and found that very little psychosine accumulated in the CNS or PNS of the mouse. As expected, demyelination with the infiltration of multinucleated macrophages (globoid cells) characteristic of Krabbe disease was milder in Twi\/Sap\u2010D KO mice than in Twi mice both in the CNS and PNS during the early disease stage. However, at the later disease stage, qualitatively and quantitatively comparable demyelination occurred in Twi\/Sap\u2010D KO mice, particularly in the PNS, and the lifespans of Twi\/Sap\u2010D KO mice were even shorter than that of Twi mice. Bone marrow\u2010derived macrophages from both Twi and Twi\/Sap\u2010D KO mice produced significant amounts of TNF\u2010\u03b1 upon exposure to GalCer and were transformed into globoid cells. These results indicate that psychosine in Krabbe disease is mainly produced via the deacylation of GalCer by ACDase. The demyelination observed in Twi\/Sap\u2010D KO mice may be mediated by a psychosine\u2010independent, Sap\u2010D\u2010dependent mechanism. GalCer\u2010induced activation of Sap\u2010D\u2010deficient macrophages\/microglia may play an important role in the neuroinflammation and demyelination in Twi\/Sap\u2010D KO mice.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15876-fig-0013-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15876","type":"journal-article","created":{"date-parts":[[2023,6,20]],"date-time":"2023-06-20T04:17:54Z","timestamp":1687234674000},"page":"720-746","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic ablation of\n                    <scp>Saposin\u2010D<\/scp>\n                    in Krabbe disease eliminates psychosine accumulation but does not significantly improve demyelination"],"prefix":"10.1111","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1696-642X","authenticated-orcid":false,"given":"Takashi","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4943-944X","authenticated-orcid":false,"given":"Kazuhito","family":"Tsuboi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuaki","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Central Research Institute Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-902X","authenticated-orcid":false,"given":"Yuta","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Go","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3533-1670","authenticated-orcid":false,"given":"Etsuko","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayaka","family":"Ono","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2966-0577","authenticated-orcid":false,"given":"Yasuo","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2079-8278","authenticated-orcid":false,"given":"Junko","family":"Matsuda","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology and Metabolism Kawasaki Medical School  Okayama Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,6,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014\u20104886(70)90075\u20100"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)69582-1"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbior.2016.10.002"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/103.3.695"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature08938"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1097\u20104547(20000115)59:2<179::aid\u2010jnr4>3.0.co;2\u2010n"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.24008"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100028\u20101091865"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M039610"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(65)80041-5"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12951"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V100.4.1454.h81602001454_1454_1464"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104464200"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0558\u201020.2021"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.149.4.943"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1994.1612"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u20108993(80)90159\u20106"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/39.1\u20102.74"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.23787"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1912108116"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02531841"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddh281"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.11.1191"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006\u2010291x(72)90381\u20106"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2022.106184"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1515\/cclm\u20102018\u20101301"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt190"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011765"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.1802\u201011.2011"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471\u20104159.1996.66031118.x"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010018\u201038127\u20109"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0076\u20106879(87)38063\u20102"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1022436928925"},{"issue":"7","key":"e_1_2_11_36_1","first-page":"385","article-title":"Krabbe's leukocystrophy (globoid cell leukodystrophy). An ultrastructural study","volume":"106","author":"Suzuki K.","year":"1970","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750\u20103639.1995.tb00601.x"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.66.2.302"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2275(20)39839-4"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003\u20109861(76)90515\u20104"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1010991420942"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20190"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2021.158972"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M106261200"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1042\/ebc20190090"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jlr.2022.100303"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.03.031"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot5080"},{"key":"e_1_2_11_49_1","volume-title":"The online metabolic and molecular bases of inherited disease","author":"Wenger D. A.","year":"2019"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1002\/(sici)1098\u20101004(1997)10:4<268::Aid\u2010humu2>3.0.Co;2\u2010d"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/0024\u20103205(76)90047\u20103"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1523\/jneurosci.5597\u201008.2009"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.2183\/pjab.85.422"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.22371"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.169.3940.64"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2003.12.126"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.01.008"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2018.09.015"}],"container-title":["Journal of Neurochemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/jnc.15876","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T17:08:38Z","timestamp":1692637718000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/jnc.15876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,20]]},"references-count":57,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,8]]}},"alternative-id":["10.1111\/jnc.15876"],"URL":"https:\/\/doi.org\/10.1111\/jnc.15876","archive":["Portico"],"relation":{},"ISSN":["0022-3042","1471-4159"],"issn-type":[{"value":"0022-3042","type":"print"},{"value":"1471-4159","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,20]]},"assertion":[{"value":"2023-02-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-05-28","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}