Microglia dysfunction caused by the loss of rhoa disrupts neuronal physiology and leads to neurodegeneration
Autor(a) principal: | |
---|---|
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/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. |
id |
RCAP_04e982613141792ff73ac0689cace7f6 |
---|---|
oai_identifier_str |
oai:recipp.ipp.pt:10400.22/16114 |
network_acronym_str |
RCAP |
network_name_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository_id_str |
7160 |
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) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
instname_str |
Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
instacron_str |
RCAAP |
institution |
RCAAP |
reponame_str |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
collection |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
repository.name.fl_str_mv |
Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
repository.mail.fl_str_mv |
|
_version_ |
1799131449023004672 |