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LIMP-2 deficiency-associated glycolipid abnormalities in mice

2025-07-08Artigo científico Acesso aberto
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datacite.subject.fosCiências Médicas
dc.contributor.authorda Silva Gaspar, Paulo Jorge Miranda
dc.contributor.authorMarques, André R.A.
dc.contributor.authorFerraz, Maria J.
dc.contributor.authorDamme, Markus
dc.contributor.authorKrame, Gertjan
dc.contributor.authorMirzaian, Mina
dc.contributor.authorGijbels, Marion
dc.contributor.authorOttenhoff, Roelef
dc.contributor.authorvan Roomen, Cindy
dc.contributor.authorOverkleeft, Herman S.
dc.contributor.authorSchwake, Michael
dc.contributor.authorHeybrock, Saskia
dc.contributor.authorMacário, Maria Carmo
dc.contributor.authorSaftig, Paul
dc.contributor.authorAerts, Johannes M.
dc.date.accessioned2026-02-04T13:30:55Z
dc.date.available2026-02-04T13:30:55Z
dc.date.issued2025-07-08
dc.descriptionTrabalho enquadrado na Newborn Screening, Metabolism & Genetics Unit, Human Genetics Department, National Institute of Health Doutor Ricardo Jorge, Porto, Portugal
dc.description.abstractGlucocerebrosidase (GCase) catalyzes the lysosomal degradation of glucosylceramide (GlcCer). GCase deficiency results in Gaucher disease (GD), a lysosomal storage disorder with characteristic hepatosplenomegaly. Transport of GCase to lysosomes is mediated by the lysosomal integral membrane protein type 2 (LIMP-2). Deficiency of LIMP-2 leads to reduced cellular GCase levels and manifests as Action Myoclonic Renal Failure Syndrome (AMRF). We investigated the cause for the markedly different symptomatology of GD and AMRF. In tissues of Limp2 − /− mice no prominent abnormalities in lysosomal enzymes were noted except for variable deficiency of GCase, as measured with enzymatic activity assay and detection of active GCase molecules with an activity-based probe. Noteworthy, in LIMP-2-deficient mice, residual GCase is remarkably high in leukocytes. GCase deficiency in tissues does not correlate with increases in GlcCer, but rather with increases in glucosylsphingosine (GlcSph) and glucosylated cholesterol (GlcChol), both glucosylated metabolites derived from GlcCer. Isolated lysosomes from hepatocytes of Limp2 − /− mice revealed no prominent abnormalities in lysosomal matrix proteins except GCase. The Limp2 − /− tritosomes showed clear increases in GlcSph and GlcChol but not in GlcCer. In conclusion, our data imply a critical role of LIMP-2 in glycosphingolipid homeostasis. Despite low GCase levels striking GlcCer accumulation is avoided in tissues of LIMP-2 deficient mice.eng
dc.description.abstractHighlights: LIMP-2 deficient tissues show a variable lack of GCase. -In LIMP-2 deficient mice, residual GCase levels are significantly reduced except in leukocytes. -Lysosomes from LIMP-2 deficient mice exhibit no significant protein abnormalities with the exception of GCase. -LIMP-2 deficient mouse tissues show clear increases in GlcSph and GlcChol but not GlcCer.eng
dc.description.sponsorshipThis work was funded by Fundaçao para a Ciencia e Tecnologia (SFRH/BD/72862/2010 to P.G) and PTDC/SAU-GMG/105344/2008. ARAM was funded by the FCT Stimulus of Scientific Employment Individual Support Call 2017 (CEECIND/01006/2017).
dc.identifier.citationBiochim Biophys Acta Mol Cell Biol Lipids. 2025 Oct;1870(7):159657. doi: 10.1016/j.bbalip.2025.159657. Epub 2025 Jul 8
dc.identifier.doi10.1016/j.bbalip.2025.159657
dc.identifier.issn1388-1981
dc.identifier.pmid40639771
dc.identifier.urihttp://hdl.handle.net/10400.18/10804
dc.language.isoeng
dc.peerreviewedyes
dc.publisherElsevier
dc.relationSFRH/BD/72862/2010
dc.relationPTDC/SAU-GMG/105344/2008
dc.relationCEECIND/01006/2017
dc.relation.hasversionhttps://www.sciencedirect.com/science/article/pii/S1388198125000654?via%3Dihub
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectCerebrosides
dc.subjectCholesterol
dc.subjectGBA
dc.subjectGaucher's Disease
dc.subjectGlucocerebrosidase
dc.subjectGlucosylceramide
dc.subjectGlucosylcholesterol
dc.subjectLIMP-2
dc.subjectLysosomes
dc.subjectMass Spectrometry
dc.subjectSCARB2
dc.subjectDoenças Genéticas
dc.titleLIMP-2 deficiency-associated glycolipid abnormalities in miceeng
dc.typejournal article
dcterms.referenceshttps://ars.els-cdn.com/content/image/1-s2.0-S1388198125000654-mmc1.docx
dcterms.referenceshttps://ars.els-cdn.com/content/image/1-s2.0-S1388198125000654-mmc2.docx
dspace.entity.typePublication
oaire.citation.issue7
oaire.citation.startPage159657
oaire.citation.titleBiochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
oaire.citation.volume1870
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
person.familyNameda Silva Gaspar
person.givenNamePaulo Jorge Miranda
person.identifier1370352
person.identifier.ciencia-id7213-8E3E-DC0D
person.identifier.orcid0000-0002-4255-0946
person.identifier.ridK-4425-2013
person.identifier.scopus-author-id57201454370
relation.isAuthorOfPublication00161b65-b2af-4d9d-8a3d-06e184813012
relation.isAuthorOfPublication.latestForDiscovery00161b65-b2af-4d9d-8a3d-06e184813012

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