Repository logo
 
Publication

Impairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signalling

2020Journal article Open access
Simple item page
dc.contributor.authorMiranda-Lourenço, Catarina
dc.contributor.authorDuarte, Sofia T.
dc.contributor.authorPalminha, Cátia
dc.contributor.authorGaspar, Cláudia
dc.contributor.authorRodrigues, Tiago M.
dc.contributor.authorMagalhães-Cardoso, Teresa
dc.contributor.authorRei, Nádia
dc.contributor.authorColino-Oliveira, Mariana
dc.contributor.authorGomes, Rui
dc.contributor.authorFerreira, Sara
dc.contributor.authorRosa, Jéssica
dc.contributor.authorXapelli, Sara
dc.contributor.authorArmstrong, Judith
dc.contributor.authorGarcía-Cazorla, Àngels
dc.contributor.authorCorreia-de-Sá, Paulo
dc.contributor.authorSebastião, Ana M
dc.contributor.authorDiógenes, Maria José
dc.date.accessioned2021-09-30T11:40:50Z
dc.date.available2021-09-30T11:40:50Z
dc.date.issued2020
dc.description© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/)pt_PT
dc.description.abstractRett syndrome (RTT; OMIM#312750) is mainly caused by mutations in the X-linked MECP2 gene (methyl-CpG-binding protein 2 gene; OMIM*300005), which leads to impairments in the brain-derived neurotrophic factor (BDNF) signalling. The boost of BDNF mediated effects would be a significant breakthrough but it has been hampered by the difficulty to administer BDNF to the central nervous system. Adenosine, an endogenous neuromodulator, may accomplish that role since through A2AR it potentiates BDNF synaptic actions in healthy animals. We thus characterized several hallmarks of the adenosinergic and BDNF signalling in RTT and explored whether A2AR activation could boost BDNF actions. For this study, the RTT animal model, the Mecp2 knockout (Mecp2-/y) (B6.129P2 (C)-Mecp2tm1.1Bird/J) mouse was used. Whenever possible, parallel data was also obtained from post-mortem brain samples from one RTT patient. Ex vivo extracellular recordings of field excitatory post-synaptic potentials in CA1 hippocampal area were performed to evaluate synaptic transmission and long-term potentiation (LTP). RT-PCR was used to assess mRNA levels and Western Blot or radioligand binding assays were performed to evaluate protein levels. Changes in cortical and hippocampal adenosine content were assessed by liquid chromatography with diode array detection (LC/DAD). Hippocampal ex vivo experiments revealed that the facilitatory actions of BDNF upon LTP is absent in Mecp2-/y mice and that TrkB full-length (TrkB-FL) receptor levels are significantly decreased. Extracts of the hippocampus and cortex of Mecp2-/y mice revealed less adenosine amount as well as less A2AR protein levels when compared to WT littermates, which may partially explain the deficits in adenosinergic tonus in these animals. Remarkably, the lack of BDNF effect on hippocampal LTP in Mecp2-/y mice was overcome by selective activation of A2AR with CGS21680. Overall, in Mecp2-/y mice there is an impairment on adenosinergic system and BDNF signalling. These findings set the stage for adenosine-based pharmacological therapeutic strategies for RTT, highlighting A2AR as a therapeutic target in this devastating pathology.pt_PT
dc.description.sponsorshipThe work was supported by a joint research grant awarded to TMR from Fundação Calouste Gulbenkian and FMUL (20130002/PEC/BG); Fundação para a Ciência e Tecnologia (FCT, AdoRett – LISBOA-01-0145-FEDER-031929/2017 and FCT SFRH/BD/118238/2016 granted to CML); Universidade de Lisboa (grant awarded by CML BD2015); the Association Française du Syndrome de Rett; Program “Educação pela Ciência” Bolsas CHLN/FMUL – GAPIC (Project No. 20190017); Twinning action (SynaNet) from the EU H2020 Programme; and the UID/BIM/50005/2019, project financed by the FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Fundos do Orçamento de Estado. The work performed at ICBAS/MedInUP by PCS and TMC was partially supported by FCT (FEDER funding, project UID/BIM/4308/2019 and UIDP/04308/2020).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationNeurobiol Dis. 2020 Nov;145:105043.pt_PT
dc.identifier.doi10.1016/j.nbd.2020.105043pt_PT
dc.identifier.eissn1095-953X
dc.identifier.issn0969-9961
dc.identifier.urihttp://hdl.handle.net/10451/49719
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationLISBOA-01-0145-FEDER-031929/2017pt_PT
dc.relationUID/BIM/4308/2019pt_PT
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/neurobiology-of-diseasept_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/pt_PT
dc.subjectAdenosinergic systempt_PT
dc.subjectBrain-derived neurotrophic factor (BDNF)pt_PT
dc.subjectMecp2 knockout modelpt_PT
dc.subjectRett syndromept_PT
dc.subjectTrkB receptorspt_PT
dc.titleImpairment of adenosinergic system in Rett syndrome: novel therapeutic target to boost BDNF signallingpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/62605/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/154779/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/157850/PT
oaire.citation.titleNeurobiology of Diseasept_PT
oaire.citation.volume145pt_PT
oaire.fundingStreamOE
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameMiranda Lourenço
person.familyNameGaspar
person.familyNameRodrigues
person.familyNameHenriques Rei
person.familyNameGomes
person.familyNameXapelli
person.familyNameSebastião
person.familyNamede Oliveira Diógenes Nogueira
person.givenNameCatarina
person.givenNameClaudia
person.givenNameTiago M.
person.givenNameNádia Raquel
person.givenNameRui
person.givenNameSara
person.givenNameAna M
person.givenNameMaria José
person.identifier703955
person.identifier129383
person.identifier.ciencia-idA815-F59B-47E2
person.identifier.ciencia-idAC18-F9C6-0D21
person.identifier.ciencia-id011D-58DF-FEAD
person.identifier.ciencia-id7110-C8C3-ED42
person.identifier.ciencia-idF112-55E8-E37E
person.identifier.ciencia-id4B10-886B-DAFC
person.identifier.orcid0000-0002-9633-7999
person.identifier.orcid0000-0003-1051-0998
person.identifier.orcid0000-0002-0973-9763
person.identifier.orcid0000-0003-0131-0126
person.identifier.orcid0000-0002-7242-6540
person.identifier.orcid0000-0001-6854-2509
person.identifier.orcid0000-0001-9030-6115
person.identifier.orcid0000-0001-5486-6246
person.identifier.ridI-6402-2013
person.identifier.ridM-1803-2015
person.identifier.scopus-author-id36991639300
person.identifier.scopus-author-id56346375100
person.identifier.scopus-author-id55512319100
person.identifier.scopus-author-id8721560200
person.identifier.scopus-author-id7004409879
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
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublicationac84bb9d-5767-4c17-bfe7-7b508cd0b804
relation.isAuthorOfPublicationa4de13f4-2209-4682-aee7-975bfff01d31
relation.isAuthorOfPublication8b4bedae-b209-434d-965f-33164fc9c726
relation.isAuthorOfPublicationf3dd3fc7-63f4-496a-b60c-dca959cf257c
relation.isAuthorOfPublication15f68298-e314-434f-9ab4-e04b884d6c9c
relation.isAuthorOfPublicationb4bd1deb-458d-4981-bd54-46ddf93a1927
relation.isAuthorOfPublication304abd7f-071b-4447-a8a3-4aa5f0547141
relation.isAuthorOfPublication15580af4-c3d5-491e-8ab5-bdc7d3c587a3
relation.isAuthorOfPublication.latestForDiscovery15f68298-e314-434f-9ab4-e04b884d6c9c
relation.isProjectOfPublication770d5ad5-6f0f-4bef-b16b-0c8d86211594
relation.isProjectOfPublication90707069-d0b0-4d72-a7b1-02aa93ac23f7
relation.isProjectOfPublicationd422b54d-7444-4ecd-b38e-33defbb887d3
relation.isProjectOfPublication.latestForDiscovery770d5ad5-6f0f-4bef-b16b-0c8d86211594

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Impairment_adenosinergic.pdf
Size:
6.16 MB
Format:
Adobe Portable Document Format
Download

Collections

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