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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.accessioned2020-07-17T10:47:29Z
dc.date.available2020-07-17T10:47:29Z
dc.date.issued2020
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.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationSocodato, R., Portugal, C. C., Canedo, T., Rodrigues, A., Almeida, T. O., Henriques, J. F., Vaz, S. H., Magalhães, J., Silva, C. M., Baptista, F. I., Alves, R. L., Coelho-Santos, V., Silva, A. P., Paes-de-Carvalho, R., Magalhães, A., Brakebusch, C., Sebastião, A. M., Summavielle, T., Ambrósio, A. F., & Relvas, J. B. (2020). Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration. Cell Reports, 31(12), 107796. https://doi.org/10.1016/j.celrep.2020.107796
dc.identifier.doi10.1016/j.celrep.2020.107796pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.22/16114
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.relationPTDC/MED-NEU/31318/2017-031318pt_PT
dc.relationPOCI-01-0145-FEDER-007440pt_PT
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/science/article/pii/S2211124720307774pt_PT
dc.subjectRhoGTPasept_PT
dc.subjectLTPpt_PT
dc.subjectMemorypt_PT
dc.subjectAlzheimer diseasept_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.awardTitleCenter for Innovative Biomedicine and Biotechnology
oaire.awardTitleCenter for Innovative Biomedicine and Biotechnology
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.startPage107796pt_PT
oaire.citation.titleCell Reportspt_PT
oaire.citation.volume31pt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameSummavielle
person.givenNameTeresa
person.identifier677706
person.identifier.ciencia-idC41E-0816-5C85
person.identifier.orcid0000-0003-2548-6281
person.identifier.ridC-9776-2012
person.identifier.scopus-author-id6603092949
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.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication207ee2de-85a0-4144-9e7e-b376c600e065
relation.isAuthorOfPublication.latestForDiscovery207ee2de-85a0-4144-9e7e-b376c600e065
relation.isProjectOfPublication94dc584c-a368-4235-b455-31066c1b9b31
relation.isProjectOfPublication5e3ad2d1-36d3-46e5-a192-7da83288a4e4
relation.isProjectOfPublication.latestForDiscovery94dc584c-a368-4235-b455-31066c1b9b31

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