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Mutant A53T α-synuclein improves rotarod performance before motor deficits and affects metabolic pathways

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dc.contributor.authorGuerreiro, Patrícia
dc.contributor.authorCoelho, Joana E
dc.contributor.authorSousa-Lima, Inês
dc.contributor.authorMacedo, Paula
dc.contributor.authorLopes, Luisa V.
dc.contributor.authorOuteiro, Tiago
dc.contributor.authorFaria Pais, Teresa
dc.date.accessioned2022-12-14T13:57:49Z
dc.date.available2022-12-14T13:57:49Z
dc.date.issued2016
dc.description© Springer Science+Business Media New York 2016pt_PT
dc.description.abstractThe protein α-synuclein (α-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether α-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human α-Syn (α-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing α-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous). At 17 months of age, α-SynA53T overexpression promoted general reduction in grip strength and deficient hindlimb reflex and resulted in severe disease and mortality in 50 % of the mice. Analysis of serum metabolites further revealed decreased levels of cholesterol, triglycerides and non-esterified fatty acids (NEFA) in α-SynA53T-overexpressing mice. In fed conditions, these mice also showed a significant decrease in serum insulin without alterations in blood glucose. In addition, assessment of inflammatory gene expression in the brain showed a significant increase in TNF-α mRNA but not of IL-1β induced by α-SynA53T overexpression. Interestingly, the brain mRNA levels of Sirtuin 2 (Sirt2), a deacetylase involved in both metabolic and inflammatory pathways, were significantly reduced. Our findings highlight the relevance of the mechanisms underlying initial weight loss and hyperactivity as early markers of synucleinopathies. Moreover, we found that changes in blood metabolites and decreased brain Sirt2 gene expression are associated with motor deficits.pt_PT
dc.description.sponsorshipThis work was funded by Fundação para a Ciência e Tecnologia, Portugal (PTDC/SAU-ORG/114083/2009). TFP was “Investigador FCT”; JEC is a postdoctoral FCT fellow (BPD/87647/2012); LVL is an “Investigador FCT”; TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNeuromolecular Med. 2017 Mar;19(1):113-121pt_PT
dc.identifier.doi10.1007/s12017-016-8435-5pt_PT
dc.identifier.eissn1559-1174
dc.identifier.issn1535-1084
dc.identifier.urihttp://hdl.handle.net/10451/55393
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationMICROGLIA DYSREGULATION AS TRIGGER FOR CHRONIC NEUROINFLAMMATION: IMPACT FOR AGING AND NEURODEGENERATIVE DISEASES
dc.relation.publisherversionhttps://www.springer.com/journal/12017pt_PT
dc.subjectLipid metabolismpt_PT
dc.subjectSirtuinspt_PT
dc.subjectSynucleinopathiespt_PT
dc.titleMutant A53T α-synuclein improves rotarod performance before motor deficits and affects metabolic pathwayspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/SAU-ORG/114083/2009
oaire.awardNumberSFRH/BPD/87647/2012
oaire.awardTitleMICROGLIA DYSREGULATION AS TRIGGER FOR CHRONIC NEUROINFLAMMATION: IMPACT FOR AGING AND NEURODEGENERATIVE DISEASES
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-ORG%2F114083%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F87647%2F2012/PT
oaire.citation.endPage121pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage113pt_PT
oaire.citation.titleNeuroMolecular Medicinept_PT
oaire.citation.volume19pt_PT
oaire.fundingStream3599-PPCDT
person.familyNameGuerreiro
person.familyNameCoelho
person.familyNameLopes
person.familyNameOuteiro
person.familyNameFaria Pais
person.givenNamePatrícia
person.givenNameJoana
person.givenNameLuisa
person.givenNameTiago
person.givenNameTeresa
person.identifier149432
person.identifier.ciencia-idB310-839B-564D
person.identifier.ciencia-id4817-7194-C024
person.identifier.ciencia-idBC14-20AB-8D68
person.identifier.ciencia-id7713-AC26-7BF3
person.identifier.orcid0000-0002-0948-043X
person.identifier.orcid0000-0002-3964-6197
person.identifier.orcid0000-0001-8367-3005
person.identifier.orcid0000-0003-1679-1727
person.identifier.orcid0000-0002-8855-4395
person.identifier.ridJ-4525-2013
person.identifier.scopus-author-id55200776400
person.identifier.scopus-author-id7101840699
person.identifier.scopus-author-id7102509159
person.identifier.scopus-author-id6602262952
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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