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Going the extra (synaptic) mile: excitotoxicity as the road toward neurodegenerative diseases

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dc.contributor.authorArmada-Moreira, Adam
dc.contributor.authorGomes, Joana I.
dc.contributor.authorPina, Carolina Campos
dc.contributor.authorSavchak, Oksana K.
dc.contributor.authorGonçalves-Ribeiro, Joana
dc.contributor.authorRei, Nádia
dc.contributor.authorPinto, Sara
dc.contributor.authorMorais, Tatiana P.
dc.contributor.authorMartins, Robertta Silva
dc.contributor.authorRibeiro, Filipa
dc.contributor.authorSebastião, Ana M
dc.contributor.authorCrunelli, Vincenzo
dc.contributor.authorVaz, Sandra H.
dc.date.accessioned2021-12-02T14:56:15Z
dc.date.available2021-12-02T14:56:15Z
dc.date.issued2020
dc.descriptionCopyright © 2020 Armada-Moreira, Gomes, Pina, Savchak, Gonçalves-Ribeiro, Rei, Pinto, Morais, Martins, Ribeiro, Sebastião, Crunelli and Vaz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.pt_PT
dc.description.abstractExcitotoxicity is a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death. In this process, the shift between normal physiological function and excitotoxicity is largely controlled by astrocytes since they can control the levels of glutamate on the synaptic cleft. This control is achieved through glutamate clearance from the synaptic cleft and its underlying recycling through the glutamate-glutamine cycle. The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress. Regardless, it is known that the excessive activation of NMDAR results in the sustained influx of calcium into neurons and leads to several deleterious consequences, including mitochondrial dysfunction, reactive oxygen species (ROS) overproduction, impairment of calcium buffering, the release of pro-apoptotic factors, among others, that inevitably contribute to neuronal loss. A large body of evidence implicates NMDAR-mediated excitotoxicity as a central mechanism in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and epilepsy. In this review article, we explore different causes and consequences of excitotoxicity, discuss the involvement of NMDAR-mediated excitotoxicity and its downstream effects on several neurodegenerative disorders, and identify possible strategies to study new aspects of these diseases that may lead to the discovery of new therapeutic approaches. With the understanding that excitotoxicity is a common denominator in neurodegenerative diseases and other disorders, a new perspective on therapy can be considered, where the targets are not specific symptoms, but the underlying cellular phenomena of the disease.pt_PT
dc.description.sponsorshipThis work was funded by Fundação para a Ciência e Tecnologia (FCT), Portugal (PTDC/BTM-SAL/32147/2017, PD/BD/114278/2016, IMM/BI/2-2020), and by FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado (UID/BIM/50005/2019). TM was funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska/Curie grant agreement No. 722053.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationFront Cell Neurosci. 2020 Apr 24;14:90pt_PT
dc.identifier.doi10.3389/fncel.2020.00090pt_PT
dc.identifier.eissn1662-5102
dc.identifier.urihttp://hdl.handle.net/10451/50245
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontierspt_PT
dc.relationIMM/BI/2-2020pt_PT
dc.relationAstrosomes: Artificial Astrocytes as a Novel Approach to Regulate Neuronal Communication
dc.relationAstrosomes: a novel approach for the regulation of neuronal communication
dc.relationInstituto de Medicina Molecular
dc.relationTraining, Research and Raising of Public Awareness in Cell Biology and Pathology of Neuroglia
dc.relation.publisherversionhttps://www.frontiersin.org/journals/cellular-neuroscience#pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectNMDA receptorspt_PT
dc.subjectAstrocytespt_PT
dc.subjectCalcium signalingpt_PT
dc.subjectExcitotoxicitypt_PT
dc.subjectNeurodegenerative diseasespt_PT
dc.subjectOxidative stresspt_PT
dc.titleGoing the extra (synaptic) mile: excitotoxicity as the road toward neurodegenerative diseasespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/BTM-SAL/32147/2017
oaire.awardNumberPD/BD/114278/2016
oaire.awardNumberUID/BIM/50005/2019
oaire.awardNumber722053
oaire.awardTitleAstrosomes: Artificial Astrocytes as a Novel Approach to Regulate Neuronal Communication
oaire.awardTitleAstrosomes: a novel approach for the regulation of neuronal communication
oaire.awardTitleInstituto de Medicina Molecular
oaire.awardTitleTraining, Research and Raising of Public Awareness in Cell Biology and Pathology of Neuroglia
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBTM-SAL%2F32147%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//PD%2FBD%2F114278%2F2016/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F50005%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/722053/EU
oaire.citation.titleFrontiers in Cellular Neurosciencept_PT
oaire.citation.volume14pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamH2020
person.familyNameArmada-Moreira
person.familyNameGomes
person.familyNameSavchak
person.familyNameGonçalves Ribeiro
person.familyNameHenriques Rei
person.familyNameCastro da Costa Pinto
person.familyNameRibeiro
person.familyNameSebastião
person.familyNameHenriques Vaz
person.givenNameAdam
person.givenNameJoana I.
person.givenNameOksana
person.givenNameJoana Filipa
person.givenNameNádia Raquel
person.givenNameSara Filipa
person.givenNameFilipa
person.givenNameAna M
person.givenNameSandra Cristina
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project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100008530
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.nameEuropean Commission
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