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Linking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cells

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dc.contributor.authorPerfeito, Rita
dc.contributor.authorLázaro, Diana F.
dc.contributor.authorOuteiro, Tiago
dc.contributor.authorRego, A. Cristina
dc.date.accessioned2022-03-04T17:29:32Z
dc.date.available2022-03-04T17:29:32Z
dc.date.issued2014
dc.description© 2014 Elsevier Inc. All rights reserved.pt_PT
dc.description.abstractAlpha-synuclein (α-syn) is a soluble protein highly enriched in presynaptic terminals of neurons. Accumulation of α-syn as intracellular filamentous aggregates is a pathological feature of sporadic and familial forms of Parkinson's disease (PD). Changes in α-syn post-translational modifications, as well as mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Here we assessed the correlation between α-syn phosphorylation at serine 129 (Ser129), the formation of reactive oxygen species (ROS) and mitochondrial dysfunction in SH-SY5Y cells expressing A53T mutant or wild-type (WT) α-syn, exposed to ferrous iron (FeSO4) and rotenone (complex I inhibitor). Under basal conditions, prolonged expression of A53T mutant α-syn altered mitochondria morphology, increased superoxide formation and phosphorylation at Ser129, which was linked to decreased activity of protein phosphatase 2A (PP2A). Exposure to FeSO4 or rotenone enhanced intracellular ROS levels, including superoxide anions, in both types of cells, along with α-syn Ser129 phosphorylation and mitochondrial depolarization. Most of these changes were largely evident in A53T mutant α-syn expressing cells. Overall, the data suggest that stimuli that promote ROS formation and mitochondrial alterations highly correlate with mutant α-syn phosphorylation at Ser129, which may precede cell degeneration in PD.pt_PT
dc.description.sponsorshipWork supported by the Fundação para a Ciência e a Tecnologia (FCT), Portugal, project references PTDC/SAU-NEU/101928/2008 and PEst-C/SAU/LA0001/2013–2014, and co-financed by “COMPETE—Programa Operacional Factores de Competitividade”, QREN, and the European Union (FEDER—Fundo Europeu de Desenvolvimento Regional). R.P. was supported by the FCT Ph.D. fellowship SFRH/BD/25515/2005. T.O. was supported by an EMBO Installation Grant and by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationMol Cell Neurosci. 2014 Sep;62:51-59pt_PT
dc.identifier.doi10.1016/j.mcn.2014.08.002pt_PT
dc.identifier.eissn1095-9327
dc.identifier.issn1044-7431
dc.identifier.urihttp://hdl.handle.net/10451/51606
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationPEst-C/SAU/LA0001/2013–2014pt_PT
dc.relationDeciphering the molecular mechanisms linking alpha-synuclein dysfunction and cytotoxicity in Parkinson's disease - the role of GDNF
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/molecular-and-cellular-neurosciencept_PT
dc.subjectAlpha-synucleinpt_PT
dc.subjectAlpha-synuclein Ser129 phosphorylationpt_PT
dc.subjectMitochondrial dysfunctionpt_PT
dc.subjectOxidative stresspt_PT
dc.subjectParkinson's diseasept_PT
dc.subjectProtein phosphatase 2Apt_PT
dc.titleLinking alpha-synuclein phosphorylation to reactive oxygen species formation and mitochondrial dysfunction in SH-SY5Y cellspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDeciphering the molecular mechanisms linking alpha-synuclein dysfunction and cytotoxicity in Parkinson's disease - the role of GDNF
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FSAU-NEU%2F101928%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F25515%2F2005/PT
oaire.citation.endPage59pt_PT
oaire.citation.startPage51pt_PT
oaire.citation.titleMolecular and Cellular Neurosciencept_PT
oaire.citation.volume62pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStreamSFRH
person.familyNameOuteiro
person.givenNameTiago
person.identifier.ciencia-idBC14-20AB-8D68
person.identifier.orcid0000-0003-1679-1727
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
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscoveryaf7b2e31-d9da-4e83-a8f1-702910f80a40
relation.isProjectOfPublication6a2054cf-dae3-40dc-8dca-dca62826cafb
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