Logo do repositório
 
Publicação

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

2021Artigo científico Acesso aberto
Ver registo simples
dc.contributor.authorBarbosa, Marta
dc.contributor.authorGomes, Cátia
dc.contributor.authorSequeira, Catarina
dc.contributor.authorGonçalves-Ribeiro, Joana
dc.contributor.authorPina, Carolina Campos
dc.contributor.authorCarvalho, Luís A.
dc.contributor.authorMoreira, Rui
dc.contributor.authorVaz, Sandra H.
dc.contributor.authorVaz, Ana Rita
dc.contributor.authorBrites, Dora
dc.date.accessioned2021-05-20T14:36:23Z
dc.date.available2021-05-20T14:36:23Z
dc.date.issued2021
dc.descriptionCopyright © 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).pt_PT
dc.description.abstractReactive 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.pt_PT
dc.description.sponsorshipThis 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.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Cell Dev Biol. 2021 Apr 23;9:634355.pt_PT
dc.identifier.doi10.3389/fcell.2021.634355pt_PT
dc.identifier.eissn2296-634X
dc.identifier.urihttp://hdl.handle.net/10451/48047
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationLISBOA-01-0145-FEDER-031395pt_PT
dc.relationDevelopment of an autologous exosome-based therapy by engineering microRNAs in microglia and motor-neurons using mice and human models of amyotrophic lateral sclerosis (ALS)
dc.relationResearch Institute for Medicines
dc.relationResearch Institute for Medicines
dc.relationELA-2015-002pt_PT
dc.relationAssessment of phenotypic modulation of ALS-­ASTRO-­TOX cells and their secretome toward motor neuron survival using new advanced experimental models
dc.relationNovel therapeutic approach to ALS: targeting aberrant-like astrocytes before transplantation
dc.relationDISSECTING THE MECHANISMS OF MICROGLIA RESPONSE, DETERMINANTS AND BIOMARKERS IN AMYOTROPHIC LATERAL SCLEROSIS
dc.relationA definir
dc.relation.publisherversionhttps://www.frontiersin.org/journals/cell-and-developmental-biologypt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAmyotrophic lateral sclerosispt_PT
dc.subjectAstrocyte-microglia communicationpt_PT
dc.subjectAstrocyte-motor neuron crosstalkpt_PT
dc.subjectCalcium signaling aberranciespt_PT
dc.subjectGlycoursodeoxycholic acidpt_PT
dc.subjectReactive astrocytespt_PT
dc.subjectSmall extracellular vesiclespt_PT
dc.subjectVinyl sulfonept_PT
dc.titleRecovery of depleted miR-146a in ALS cortical astrocytes reverts cell aberrancies and prevents paracrine pathogenicity on microglia and motor neuronspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDevelopment of an autologous exosome-based therapy by engineering microRNAs in microglia and motor-neurons using mice and human models of amyotrophic lateral sclerosis (ALS)
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleResearch Institute for Medicines
oaire.awardTitleAssessment of phenotypic modulation of ALS-­ASTRO-­TOX cells and their secretome toward motor neuron survival using new advanced experimental models
oaire.awardTitleNovel therapeutic approach to ALS: targeting aberrant-like astrocytes before transplantation
oaire.awardTitleDISSECTING THE MECHANISMS OF MICROGLIA RESPONSE, DETERMINANTS AND BIOMARKERS IN AMYOTROPHIC LATERAL SCLEROSIS
oaire.awardTitleA definir
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FMED-NEU%2F31395%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMED-QUI%2F30021%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDP%2F04138%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F129586%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F102718%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F76590%2F2011/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/PD%2FBD%2F150342%2F2019/PT
oaire.citation.titleFrontiers in Cell and Developmental Biologypt_PT
oaire.citation.volume9pt_PT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
oaire.fundingStreamOE
person.familyNameGonçalves Ribeiro
person.familyNameHenriques Vaz
person.givenNameJoana Filipa
person.givenNameSandra Cristina
person.identifier.ciencia-id3018-692A-C792
person.identifier.ciencia-id0E1C-952D-61BE
person.identifier.orcid0000-0002-5194-6512
person.identifier.orcid0000-0003-4258-9397
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationda4877e2-3db5-486c-99cd-ca4398e0f9d3
relation.isAuthorOfPublicationb282e0fa-69eb-4079-8752-b7dd914f7745
relation.isAuthorOfPublication.latestForDiscoveryda4877e2-3db5-486c-99cd-ca4398e0f9d3
relation.isProjectOfPublication0eb70aed-a985-483f-806e-265eff7e8192
relation.isProjectOfPublicationd077bdcf-8aba-4492-9206-290959cf8d68
relation.isProjectOfPublicationbb00962c-ed82-4d7a-bc37-61df49767d93
relation.isProjectOfPublicationa21e6964-b01b-421e-9356-1ff6579cdd5c
relation.isProjectOfPublication9b5fe896-5b6e-43da-8e64-8aea3d308a12
relation.isProjectOfPublication0154f122-a0fc-4eb2-807a-0fc37b74d9db
relation.isProjectOfPublication7ad4a241-3930-4c7a-9b6f-d91e64f61d45
relation.isProjectOfPublicationb3bacef8-f2b7-48fb-a2c6-4ea31c2f0a0b
relation.isProjectOfPublication.latestForDiscovery9b5fe896-5b6e-43da-8e64-8aea3d308a12

Ficheiros

Principais
A mostrar 1 - 1 de 1
Miniatura
Nome:
Recovery_miR-146a.pdf
Tamanho:
6.48 MB
Formato:
Adobe Portable Document Format
Ver/Abrir

Coleções

IMM - Artigos em Revistas Internacionais
FM-IFN-Artigos em Revistas Internacionais