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Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration

2020Journal article Open access
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dc.contributor.authorSocodato, Renato
dc.contributor.authorPortugal, Camila C.
dc.contributor.authorCanedo, Teresa
dc.contributor.authorRodrigues, Artur
dc.contributor.authorAlmeida, Tiago O.
dc.contributor.authorHenriques, Joana F.
dc.contributor.authorVaz, Sandra H.
dc.contributor.authorMagalhães, João
dc.contributor.authorSilva, Cátia M.
dc.contributor.authorBaptista, Filipa I.
dc.contributor.authorAlves, Renata L.
dc.contributor.authorCoelho-Santos, Vanessa
dc.contributor.authorSilva, Ana Paula
dc.contributor.authorPaes de Carvalho, Roberto
dc.contributor.authorMagalhães, Ana
dc.contributor.authorBrakebusch, Cord
dc.contributor.authorSebastião, Ana M
dc.contributor.authorSummavielle, Teresa
dc.contributor.authorAmbrósio, António F.
dc.contributor.authorRelvas, João B.
dc.date.accessioned2021-07-23T15:24:25Z
dc.date.available2021-07-23T15:24:25Z
dc.date.issued2020
dc.description© 2020 The Author(s). Creative Commons Attribution (CC BY 4.0)pt_PT
dc.description.abstractNervous tissue homeostasis requires the regulation of microglia activity. Using conditional gene targeting in mice, we demonstrate that genetic ablation of the small GTPase Rhoa in adult microglia is sufficient to trigger spontaneous microglia activation, producing a neurological phenotype (including synapse and neuron loss, impairment of long-term potentiation [LTP], formation of β-amyloid plaques, and memory deficits). Mechanistically, loss of Rhoa in microglia triggers Src activation and Src-mediated tumor necrosis factor (TNF) production, leading to excitotoxic glutamate secretion. Inhibiting Src in microglia Rhoa-deficient mice attenuates microglia dysregulation and the ensuing neurological phenotype. We also find that the Rhoa/Src signaling pathway is disrupted in microglia of the APP/PS1 mouse model of Alzheimer disease and that low doses of Aβ oligomers trigger microglia neurotoxic polarization through the disruption of Rhoa-to-Src signaling. Overall, our results indicate that disturbing Rho GTPase signaling in microglia can directly cause neurodegeneration.pt_PT
dc.description.sponsorshipThe authors acknowledge the support of the following i3S Scientific Platforms: Animal Facility, Translational Cytometry Unit (TraCy), BioSciences Screening (BS) and Advanced Light Microscopy (ALM), and members of the national infrastructure PPBI-Portuguese Platform of BioImaging (supported by POCI-01–0145-FEDER-022122). FCT Portugal ( PTDC/MED-NEU/31318/2017-031318 ) supported work in the J.B.R. lab. FCT Portugal , PEst ( UID/NEU/04539/2013 ), COMPETE-FEDER ( POCI-01-0145-FEDER-007440 ), Centro 2020 Regional Operational Programme ( CENTRO-01-0145-FEDER-000008 : BrainHealth 2020), and Strategic Project UIDB/04539/2020 and UIDP/04539/2020 (CIBB) supported work in the A.F.A. lab. C.C.P. and R.S. hold employment contracts financed by national funds through FCT (Fundação para a Ciência e a Tecnologia, I.P.) in the context of the program contract described in paragraphs 4, 5, and 6 of article 23 of law no. 57/2016, of August 29th, as amended by law no. 57/2017 of July 19th.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationCell Rep. 2020 Jun 23;31(12):107796pt_PT
dc.identifier.doi10.1016/j.celrep.2020.107796pt_PT
dc.identifier.eissn2211-1247
dc.identifier.urihttp://hdl.handle.net/10451/49091
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationPOCI-01–0145-FEDER-022122pt_PT
dc.relationPTDC/MED-NEU/31318/2017-031318pt_PT
dc.relationCNC. IBILI
dc.relationCENTRO-01-0145-FEDER-000008pt_PT
dc.relationCenter for Innovative Biomedicine and Biotechnology
dc.relationCenter for Innovative Biomedicine and Biotechnology
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/cell-reportspt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAlzheimer diseasept_PT
dc.subjectLTPpt_PT
dc.subjectRhoGTPasept_PT
dc.subjectMemorypt_PT
dc.subjectTyrosine kinasept_PT
dc.titleMicroglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegenerationpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleCNC. IBILI
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FNEU%2F04539%2F2013/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04539%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04539%2F2020/PT
oaire.citation.issue12pt_PT
oaire.citation.titleCell Reportspt_PT
oaire.citation.volume31pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameHenriques Vaz
person.familyNameSebastião
person.givenNameSandra Cristina
person.givenNameAna M
person.identifier.ciencia-id0E1C-952D-61BE
person.identifier.ciencia-idF112-55E8-E37E
person.identifier.orcid0000-0003-4258-9397
person.identifier.orcid0000-0001-9030-6115
person.identifier.scopus-author-id7004409879
project.funder.identifierhttp://doi.org/10.13039/501100001871
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
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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