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Coenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher disease

2017-02-06Journal article Open access
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dc.contributor.authorMata, Mario de la
dc.contributor.authorCotán, David
dc.contributor.authorOropesa-Ávila, Manuel
dc.contributor.authorVillanueva-Paz, Marina
dc.contributor.authorLavera, Isabel de
dc.contributor.authorÁlvarez-Córdoba, Mónica
dc.contributor.authorLuzón-Hidalgo, Raquel
dc.contributor.authorSuárez-Rivero, Juan M.
dc.contributor.authorTiscornia, Gustavo
dc.contributor.authorSánchez-Alcázar, José A.
dc.date.accessioned2017-03-07T10:01:15Z
dc.date.available2017-03-07T10:01:15Z
dc.date.issued2017-02-06
dc.date.updated2017-02-06T17:04:06Z
dc.description.abstractBackground Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal β-glucocerebrosidase (GCase). In GD, partial or complete loss of GCase activity causes the accumulation of the glycolipids glucosylceramide (GlcCer) and glucosylsphingosine in the lysosomes of macrophages. In this manuscript, we investigated the effects of glycolipids accumulation on lysosomal and mitochondrial function, inflammasome activation and efferocytosis capacity in a THP-1 macrophage model of Gaucher disease. In addition, the beneficial effects of coenzyme Q10 (CoQ) supplementation on cellular alterations were evaluated. Chemically-induced Gaucher macrophages were developed by differentiateing THP-1 monocytes to macrophages by treatment with phorbol 12-myristate 13-acetate (PMA) and then inhibiting intracellular GCase with conduritol B-epoxide (CBE), a specific irreversible inhibitor of GCase activity, and supplementing the medium with exogenous GlcCer. This cell model accumulated up to 16-fold more GlcCer compared with control THP-1 cells. Results Chemically-induced Gaucher macrophages showed impaired autophagy flux associated with mitochondrial dysfunction and increased oxidative stress, inflammasome activation and impaired efferocytosis. All abnormalities were partially restored by supplementation with CoQ. Conclusion These data suggest that targeting mitochondria function and oxidative stress by CoQ can ameliorate the pathological phenotype of Gaucher cells. Chemically-induced Gaucher macrophages provide cellular models that can be used to investigate disease pathogenesis and explore new therapeutics for GD.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationOrphanet Journal of Rare Diseases. 2017 Feb 06;12(1):23pt_PT
dc.identifier.doihttp://dx.doi.org/10.1186/s13023-017-0574-8pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.1/9015
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherBioMed Centralpt_PT
dc.rights.holderThe Author(s).
dc.subjectGaucher diseasept_PT
dc.subjectInflammasomept_PT
dc.subjectEfferocytosispt_PT
dc.subjectOxidative stresspt_PT
dc.subjectMitochondriapt_PT
dc.subjectCoenzyme Q10pt_PT
dc.titleCoenzyme Q10 partially restores pathological alterations in a macrophage model of Gaucher diseasept_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue(1):23pt_PT
oaire.citation.titleOrphanet Journal of Rare Diseasespt_PT
oaire.citation.volume12pt_PT
person.familyNameTiscornia
person.givenNameGustavo
person.identifier.ciencia-id7818-59E3-E4EE
person.identifier.orcid0000-0002-1841-5330
person.identifier.scopus-author-id6507863404
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication8d2c4950-f020-4c0c-bbbd-52d19e1397a4
relation.isAuthorOfPublication.latestForDiscovery8d2c4950-f020-4c0c-bbbd-52d19e1397a4

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