Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons

Detalhes bibliográficos
Autor(a) principal: Barbosa, Marta
Data de Publicação: 2021
Outros Autores: Gomes, Cátia, Sequeira, Catarina, Gonçalves-Ribeiro, Joana, Pina, Carolina Campos, Carvalho, Luís A., Moreira, Rui, Vaz, Sandra H., Vaz, Ana Rita, Brites, Dora
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: http://hdl.handle.net/10451/48047
Resumo: Copyright © 2021 Barbosa, Gomes, Sequeira, Gonçalves-Ribeiro, Pina, Carvalho, Moreira, Vaz, Vaz and Brites. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
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spelling Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neuronsAmyotrophic lateral sclerosisAstrocyte-microglia communicationAstrocyte-motor neuron crosstalkCalcium signaling aberranciesGlycoursodeoxycholic acidReactive astrocytesSmall extracellular vesiclesVinyl sulfoneCopyright © 2021 Barbosa, Gomes, Sequeira, Gonçalves-Ribeiro, Pina, Carvalho, Moreira, Vaz, Vaz and Brites. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).Reactive astrocytes in Amyotrophic Lateral Sclerosis (ALS) change their molecular expression pattern and release toxic factors that contribute to neurodegeneration and microglial activation. We and others identified a dysregulated inflammatory miRNA profile in ALS patients and in mice models suggesting that they represent potential targets for therapeutic intervention. Such cellular miRNAs are known to be released into the secretome and to be carried by small extracellular vesicles (sEVs), which may be harmful to recipient cells. Thus, ALS astrocyte secretome may disrupt cell homeostasis and impact on ALS pathogenesis. Previously, we identified a specific aberrant signature in the cortical brain of symptomatic SOD1-G93A (mSOD1) mice, as well as in astrocytes isolated from the same region of 7-day-old mSOD1 mice, with upregulated S100B/HMGB1/Cx43/vimentin and downregulated GFAP. The presence of downregulated miR-146a on both cases suggests that it can be a promising target for modulation in ALS. Here, we upregulated miR-146a with pre-miR-146a, and tested glycoursodeoxycholic acid (GUDCA) and dipeptidyl vinyl sulfone (VS) for their immunoregulatory properties. VS was more effective in restoring astrocytic miR-146a, GFAP, S100B, HMGB1, Cx43, and vimentin levels than GUDCA, which only recovered Cx43 and vimentin mRNA. The miR-146a inhibitor generated typical ALS aberrancies in wild type astrocytes that were abolished by VS. Similarly, pre-miR-146a transfection into the mSOD1 astrocytes abrogated aberrant markers and intracellular Ca2+ overload. Such treatment counteracted miR-146a depletion in sEVs and led to secretome-mediated miR-146a enhancement in NSC-34-motor neurons (MNs) and N9-microglia. Secretome from mSOD1 astrocytes increased early/late apoptosis and FGFR3 mRNA in MNs and microglia, but not when derived from pre-miR-146a or VS-treated cells. These last strategies prevented the impairment of axonal transport and synaptic dynamics by the pathological secretome, while also averted microglia activation through either secretome, or their isolated sEVs. Proteomic analysis of the target cells indicated that pre-miR-146a regulates mitochondria and inflammation via paracrine signaling. We demonstrate that replenishment of miR-146a in mSOD1 cortical astrocytes with pre-miR-146a or by VS abrogates their phenotypic aberrancies and paracrine deleterious consequences to MNs and microglia. These results propose miR-146a as a new causal and emerging therapeutic target for astrocyte pathogenic processes in ALS.This work was supported by the Research Grant of the Santa Casa Scientific Research Program on ALS, by Santa Casa da Misericórdia de Lisboa (SCML), Portugal, Project Ref. ELA-2015-002 (to DB). Fundação para a Ciência e a Tecnologia (FCT) also supported the project PTDC/MED-NEU/31395/2017 (to DB), PTDC/MED-QUI/30021/2017 (to RM) and iMed. ULisboa (UIDB/04138/2020 and UIDP/04138/2020), together with Programa Operacional Regional de Lisboa and the Programa Operacional Competitividade e Internacionalização (LISBOA-01-0145-FEDER-031395 to DB). Individual fellowships MB (SFRH/BD/129586/2017), CG (SFRH/BD/102718/2014), AV (SFRH/BPD/76590/2011), and JG-R PD/BD/150342/2019 were from FCT. CS was a research fellowship recipient from SCML.FrontiersRepositório da Universidade de LisboaBarbosa, MartaGomes, CátiaSequeira, CatarinaGonçalves-Ribeiro, JoanaPina, Carolina CamposCarvalho, Luís A.Moreira, RuiVaz, Sandra H.Vaz, Ana RitaBrites, Dora2021-05-20T14:36:23Z20212021-01-01T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/10451/48047engFront Cell Dev Biol. 2021 Apr 23;9:634355.10.3389/fcell.2021.6343552296-634Xinfo: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:RCAAP2023-11-08T16:51:14Zoai:repositorio.ul.pt:10451/48047Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-19T21:59:58.380318Repositório 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 Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
title Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
spellingShingle Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
Barbosa, Marta
Amyotrophic lateral sclerosis
Astrocyte-microglia communication
Astrocyte-motor neuron crosstalk
Calcium signaling aberrancies
Glycoursodeoxycholic acid
Reactive astrocytes
Small extracellular vesicles
Vinyl sulfone
title_short Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
title_full Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
title_fullStr Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
title_full_unstemmed Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
title_sort Recovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neurons
author Barbosa, Marta
author_facet Barbosa, Marta
Gomes, Cátia
Sequeira, Catarina
Gonçalves-Ribeiro, Joana
Pina, Carolina Campos
Carvalho, Luís A.
Moreira, Rui
Vaz, Sandra H.
Vaz, Ana Rita
Brites, Dora
author_role author
author2 Gomes, Cátia
Sequeira, Catarina
Gonçalves-Ribeiro, Joana
Pina, Carolina Campos
Carvalho, Luís A.
Moreira, Rui
Vaz, Sandra H.
Vaz, Ana Rita
Brites, Dora
author2_role 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 Barbosa, Marta
Gomes, Cátia
Sequeira, Catarina
Gonçalves-Ribeiro, Joana
Pina, Carolina Campos
Carvalho, Luís A.
Moreira, Rui
Vaz, Sandra H.
Vaz, Ana Rita
Brites, Dora
dc.subject.por.fl_str_mv Amyotrophic lateral sclerosis
Astrocyte-microglia communication
Astrocyte-motor neuron crosstalk
Calcium signaling aberrancies
Glycoursodeoxycholic acid
Reactive astrocytes
Small extracellular vesicles
Vinyl sulfone
topic Amyotrophic lateral sclerosis
Astrocyte-microglia communication
Astrocyte-motor neuron crosstalk
Calcium signaling aberrancies
Glycoursodeoxycholic acid
Reactive astrocytes
Small extracellular vesicles
Vinyl sulfone
description Copyright © 2021 Barbosa, Gomes, Sequeira, Gonçalves-Ribeiro, Pina, Carvalho, Moreira, Vaz, Vaz and Brites. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).
publishDate 2021
dc.date.none.fl_str_mv 2021-05-20T14:36:23Z
2021
2021-01-01T00:00:00Z
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/10451/48047
url http://hdl.handle.net/10451/48047
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Front Cell Dev Biol. 2021 Apr 23;9:634355.
10.3389/fcell.2021.634355
2296-634X
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.publisher.none.fl_str_mv Frontiers
publisher.none.fl_str_mv Frontiers
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
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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
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