Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegeneration
| Autor(a) principal: | |
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| Data de Publicação: | 2020 |
| Outros Autores: | , , , , , , , , , , , , , , , , , , |
| Tipo de documento: | Artigo |
| Idioma: | eng |
| Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
| Texto Completo: | http://hdl.handle.net/10451/49091 |
Resumo: | © 2020 The Author(s). Creative Commons Attribution (CC BY 4.0) |
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Microglia dysfunction caused by the loss of Rhoa disrupts neuronal physiology and leads to neurodegenerationAlzheimer diseaseLTPRhoGTPaseMemoryTyrosine kinase© 2020 The Author(s). Creative Commons Attribution (CC BY 4.0)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.The 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.ElsevierRepositório da Universidade de LisboaSocodato, 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 MSummavielle, TeresaAmbrósio, António F.Relvas, João B.2021-07-23T15:24:25Z20202020-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/49091engCell Rep. 2020 Jun 23;31(12):10779610.1016/j.celrep.2020.1077962211-1247info: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:RCAAP2023-11-08T16:52:27Zoai:repositorio.ul.pt:10451/49091Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T22:00:39.938133Repositório 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 Alzheimer disease LTP RhoGTPase Memory 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 da Universidade de Lisboa |
| 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 |
Alzheimer disease LTP RhoGTPase Memory Tyrosine kinase |
| topic |
Alzheimer disease LTP RhoGTPase Memory Tyrosine kinase |
| description |
© 2020 The Author(s). Creative Commons Attribution (CC BY 4.0) |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020-01-01T00:00:00Z 2021-07-23T15:24:25Z |
| dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/article |
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article |
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publishedVersion |
| dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10451/49091 |
| url |
http://hdl.handle.net/10451/49091 |
| dc.language.iso.fl_str_mv |
eng |
| language |
eng |
| dc.relation.none.fl_str_mv |
Cell Rep. 2020 Jun 23;31(12):107796 10.1016/j.celrep.2020.107796 2211-1247 |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
| dc.publisher.none.fl_str_mv |
Elsevier |
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Elsevier |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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