Microglia Dysfunction Caused by the Loss of Rhoa Disrupts Neuronal Physiology and Leads to Neurodegeneration
| Autor: | Ana Magalhães, Teresa Canedo, Renata L. Alves, Ana M. F. P. Silva, Sandra H. Vaz, Tiago Almeida, Renato Socodato, Cátia M. Silva, Ana M. Sebastião, João B. Relvas, António F. Ambrósio, Cord Brakebusch, Joana F. Henriques, Roberto Paes-de-Carvalho, Teresa Summavielle, Filipa I. Baptista, João P. Magalhães, Artur Rodrigues, Camila C. Portugal, Vanessa Coelho-Santos |
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| Přispěvatelé: | Instituto de Investigação e Inovação em Saúde, Repositório Científico do Instituto Politécnico do Porto, Repositório da Universidade de Lisboa |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Aging RHOA CSK Tyrosine-Protein Kinase Synapse 0302 clinical medicine rhoA GTP-Binding Protein / metabolism Aging / metabolism RhoGTPase Neurons 0303 health sciences Glutamate secretion biology Microglia Chemistry Neurons / metabolism Neurodegeneration Glutamate receptor Cell Polarity src-Family Kinases / metabolism Long-term potentiation rhoA GTP-Binding Protein / deficiency Cell biology src-Family Kinases Phenotype medicine.anatomical_structure Microglia / metabolism Signal transduction LTP Alzheimer disease Proto-oncogene tyrosine-protein kinase Src Cell Survival Nerve Degeneration / pathology General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Memory medicine Animals Tyrosine kinase 030304 developmental biology Amyloid beta-Peptides Microglia / pathology src-Family Kinases / antagonists & inhibitors Amyloid beta-Peptides / metabolism Nervous tissue medicine.disease Synapses / metabolism Mice Inbred C57BL 030104 developmental biology nervous system Synaptic plasticity Nerve Degeneration Synapses biology.protein rhoA GTP-Binding Protein Aging / pathology 030217 neurology & neurosurgery |
| Zdroj: | 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, vol. 31, no. 12, 107796, pp. 1-29 . https://doi.org/10.1016/j.celrep.2020.107796 Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Cell Reports |
| DOI: | 10.1016/j.celrep.2020.107796 |
| Popis: | © 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. |
| Databáze: | OpenAIRE |
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