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

Detalhes bibliográficos
Autor(a) principal: Socodato, Renato
Data de Publicação: 2020
Outros Autores: Portugal, Camila C., Canedo, Teresa, Rodrigues, Artur, Almeida, Tiago O., Henriques, Joana F., Vaz, Sandra H., Magalhães, João, Silva, Cátia M., Baptista, Filipa I., Alves, Renata L., Coelho-Santos, Vanessa, Silva, Ana Paula, Paes-de-Carvalho, Roberto, Magalhães, Ana, Brakebusch, Cord, Sebastião, Ana M., Summavielle, Teresa, Ambrósio, António F., Relvas, João B.
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10400.22/16114
Resumo: Nervous 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.
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spelling Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegenerationRhoGTPaseLTPMemoryAlzheimer diseaseTyrosine kinaseNervous 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.Repositório Científico do Instituto Politécnico do PortoSocodato, RenatoPortugal, Camila C.Canedo, TeresaRodrigues, ArturAlmeida, Tiago O.Henriques, Joana F.Vaz, Sandra H.Magalhães, JoãoSilva, Cátia M.Baptista, Filipa I.Alves, Renata L.Coelho-Santos, VanessaSilva, Ana PaulaPaes-de-Carvalho, RobertoMagalhães, AnaBrakebusch, CordSebastião, Ana M.Summavielle, TeresaAmbrósio, António F.Relvas, João B.2020-07-17T10:47:29Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10400.22/16114engSocodato, 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.2020.10779610.1016/j.celrep.2020.107796info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2023-12-20T01:54:23Zoai:recipp.ipp.pt:10400.22/16114Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T17:35:49.816448Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
title Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
spellingShingle Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
Socodato, Renato
RhoGTPase
LTP
Memory
Alzheimer disease
Tyrosine kinase
title_short Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
title_full Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
title_fullStr Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
title_full_unstemmed Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
title_sort Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
author Socodato, Renato
author_facet Socodato, Renato
Portugal, Camila C.
Canedo, Teresa
Rodrigues, Artur
Almeida, Tiago O.
Henriques, Joana F.
Vaz, Sandra H.
Magalhães, João
Silva, Cátia M.
Baptista, Filipa I.
Alves, Renata L.
Coelho-Santos, Vanessa
Silva, Ana Paula
Paes-de-Carvalho, Roberto
Magalhães, Ana
Brakebusch, Cord
Sebastião, Ana M.
Summavielle, Teresa
Ambrósio, António F.
Relvas, João B.
author_role author
author2 Portugal, Camila C.
Canedo, Teresa
Rodrigues, Artur
Almeida, Tiago O.
Henriques, Joana F.
Vaz, Sandra H.
Magalhães, João
Silva, Cátia M.
Baptista, Filipa I.
Alves, Renata L.
Coelho-Santos, Vanessa
Silva, Ana Paula
Paes-de-Carvalho, Roberto
Magalhães, Ana
Brakebusch, Cord
Sebastião, Ana M.
Summavielle, Teresa
Ambrósio, António F.
Relvas, João B.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Repositório Científico do Instituto Politécnico do Porto
dc.contributor.author.fl_str_mv Socodato, Renato
Portugal, Camila C.
Canedo, Teresa
Rodrigues, Artur
Almeida, Tiago O.
Henriques, Joana F.
Vaz, Sandra H.
Magalhães, João
Silva, Cátia M.
Baptista, Filipa I.
Alves, Renata L.
Coelho-Santos, Vanessa
Silva, Ana Paula
Paes-de-Carvalho, Roberto
Magalhães, Ana
Brakebusch, Cord
Sebastião, Ana M.
Summavielle, Teresa
Ambrósio, António F.
Relvas, João B.
dc.subject.por.fl_str_mv RhoGTPase
LTP
Memory
Alzheimer disease
Tyrosine kinase
topic RhoGTPase
LTP
Memory
Alzheimer disease
Tyrosine kinase
description Nervous 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.
publishDate 2020
dc.date.none.fl_str_mv 2020-07-17T10:47:29Z
2020
2020-01-01T00:00:00Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://hdl.handle.net/10400.22/16114
url http://hdl.handle.net/10400.22/16114
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Socodato, 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
10.1016/j.celrep.2020.107796
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
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