Please use this identifier to cite or link to this item: https://hdl.handle.net/10316/41106
DC FieldValueLanguage
dc.contributor.authorNaia, Luana-
dc.contributor.authorFerreira, I. Luísa-
dc.contributor.authorCunha-Oliveira, Teresa-
dc.contributor.authorDuarte, Ana I.-
dc.contributor.authorRibeiro, Márcio-
dc.contributor.authorRosenstock, Tatiana R.-
dc.contributor.authorLaço, Mário N.-
dc.contributor.authorRibeiro, Maria J.-
dc.contributor.authorOliveira, Catarina R.-
dc.contributor.authorSaudou, Frédéric-
dc.contributor.authorHumbert, Sandrine-
dc.contributor.authorRego, A. Cristina-
dc.date.accessioned2017-05-03T19:23:20Z-
dc.date.available2017-05-03T19:23:20Z-
dc.date.issued2015-02-
dc.identifier.urihttps://hdl.handle.net/10316/41106-
dc.description.abstractHuntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.por
dc.language.isoengpor
dc.rightsopenAccesspor
dc.subjectAnimalspor
dc.subjectCalciumpor
dc.subjectCell Linepor
dc.subjectCytochromes cpor
dc.subjectElectron Transportpor
dc.subjectExtracellular Signal-Regulated MAP Kinasespor
dc.subjectFemalepor
dc.subjectHumanspor
dc.subjectHuntingtin Proteinpor
dc.subjectHuntington Diseasepor
dc.subjectInsulinpor
dc.subjectInsulin-Like Growth Factor Ipor
dc.subjectLymphocytespor
dc.subjectMalepor
dc.subjectMembrane Potential, Mitochondrialpor
dc.subjectMitochondriapor
dc.subjectNerve Tissue Proteinspor
dc.subjectOxygen Consumptionpor
dc.subjectPhosphorylationpor
dc.subjectReceptor, IGF Type 1por
dc.subjectSus scrofapor
dc.subjectEnergy Metabolismpor
dc.subjectSignal Transductionpor
dc.titleActivation of IGF-1 and Insulin Signaling Pathways Ameliorate Mitochondrial Function and Energy Metabolism in Huntington’s Disease Human Lymphoblastspor
dc.typearticle-
degois.publication.firstPage331por
degois.publication.lastPage348por
degois.publication.issue1por
degois.publication.titleMolecular Neurobiologypor
dc.peerreviewedyespor
dc.identifier.doi10.1007/s12035-014-8735-4por
dc.identifier.doi10.1007/s12035-014-8735-4-
degois.publication.volume51por
item.cerifentitytypePublications-
item.languageiso639-1en-
item.fulltextCom Texto completo-
item.grantfulltextopen-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.openairetypearticle-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.researchunitCNC - Center for Neuroscience and Cell Biology-
crisitem.author.orcid0000-0002-0886-4634-
crisitem.author.orcid0000-0001-6552-4479-
crisitem.author.orcid0000-0002-7382-0339-
crisitem.author.orcid0000-0001-6422-3279-
crisitem.author.orcid0000-0001-6942-4328-
crisitem.author.orcid0000-0003-0700-3776-
Appears in Collections:I&D CNC - Artigos em Revistas Internacionais
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