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Coenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease

2017-02Artigo científico Acesso aberto
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dc.contributor.authorde la Mata, Mario
dc.contributor.authorCotan, David
dc.contributor.authorOropesa-Avila, Manuel
dc.contributor.authorVillanueva-Paz, Marina
dc.contributor.authorde lavera, Isabel
dc.contributor.authorAlvarez-Cordoba, Monica
dc.contributor.authorLuzón-Hidalgo, Raquel
dc.contributor.authorSuarez-Rivero, Juan M.
dc.contributor.authorTiscornia, Gustavo
dc.contributor.authorSanchez-Alcazar, José A.
dc.date.accessioned2018-12-07T14:53:03Z
dc.date.available2018-12-07T14:53:03Z
dc.date.issued2017-02
dc.description.abstractBackground: Gaucher disease (GD) is caused by mutations in the GBA1 gene which encodes lysosomal beta-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 Q(10) (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.
dc.description.sponsorshipFIS [PI13/00129]; Instituto de Salud Carlos III, Spain; Fondo Europeo de Desarrollo Regional (FEDER-Union Europea); Proyecto de Investigacion de Excelencia de la Junta de Andalucia [CTS-5725]; AEPMI (Asociacion de Enfermos de Patologia Mitocondrial); ENACH (Asociacion de Enfermos de Neurodegeneracion con Acumulacion Cerebral de Hierro)
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doihttps://doi.org/10.1186/s13023-017-0574-8
dc.identifier.issn1750-1172
dc.identifier.urihttp://hdl.handle.net/10400.1/11333
dc.language.isoeng
dc.peerreviewedyes
dc.publisherBiomed Central
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectTriggers mitochondria degradation
dc.subjectLysosomal storage disorders
dc.subjectParkinsons disease
dc.subjectMouse model
dc.subjectDysfunction
dc.subjectDeficiency
dc.subjectMitophagy
dc.subjectAutophagy
dc.subjectMice
dc.subjectAccumulation
dc.subjectGaucher disease
dc.subjectCoenzyme Q10
dc.subjectMitochondria
dc.subjectOxidative stress
dc.subjectInflammasome
dc.subjectEfferocytosis
dc.titleCoenzyme Q(10) partially restores pathological alterations in a macrophage model of Gaucher disease
dc.typejournal article
dspace.entity.typePublication
oaire.citation.startPage23
oaire.citation.titleOrphanet Journal of Rare Diseases
oaire.citation.volume12
person.familyNameTiscornia
person.givenNameGustavo
person.identifier.ciencia-id7818-59E3-E4EE
person.identifier.orcid0000-0002-1841-5330
person.identifier.scopus-author-id6507863404
rcaap.rightsopenAccess
rcaap.typearticle
relation.isAuthorOfPublication8d2c4950-f020-4c0c-bbbd-52d19e1397a4
relation.isAuthorOfPublication.latestForDiscovery8d2c4950-f020-4c0c-bbbd-52d19e1397a4

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