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Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

2017-05Journal article Restricted access
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dc.contributor.authorMiranda, Hugo Vicente
dc.contributor.authorSzegő, Éva M.
dc.contributor.authorOliveira, Luís M. A.
dc.contributor.authorBreda, Carlo
dc.contributor.authorDarendelioglu, Ekrem
dc.contributor.authorOliveira, Rita M. de
dc.contributor.authorFerreira, Diana G.
dc.contributor.authorGomes, Marcos A.
dc.contributor.authorRott, Ruth
dc.contributor.authorOliveira, Márcia
dc.contributor.authorMunari, Francesca
dc.contributor.authorEnguita, Francisco J.
dc.contributor.authorSimões, Tânia
dc.contributor.authorRodrigues, Eva F.
dc.contributor.authorHeinrich, Michael
dc.contributor.authorMartins, Ivo C.
dc.contributor.authorZamolo, Irina
dc.contributor.authorRiess, Olaf
dc.contributor.authorCordeiro, Carlos
dc.contributor.authorPonces-Freire, Ana
dc.contributor.authorSantos, Nuno C.
dc.contributor.authorLopes, Luisa V.
dc.contributor.authorXiang, Wei
dc.contributor.authorJovin, Thomas M.
dc.contributor.authorPenque, Deborah
dc.contributor.authorEngelender, Simone
dc.contributor.authorZweckstetter, Markus
dc.contributor.authorKlucken, Jochen
dc.contributor.authorGiorgini, Flaviano
dc.contributor.authorQuintas, Alexandre
dc.contributor.authorOuteiro, Tiago F.
dc.date.accessioned2017-11-20T15:45:17Z
dc.date.available2017-11-20T15:45:17Z
dc.date.issued2017-05
dc.description.abstractα-Synuclein misfolding and aggregation is a hallmark in Parkinson’s disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of α-synuclein are conserved from yeast to man, but the precise underpinnings of the cellular pathologies associated are still elusive, complicating the development of effective therapeutic strategies. Combining molecular genetics with target-based approaches, we established that glycation, an unavoidable age-associated post-translational modification, enhanced α-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of α-synuclein, reducing membrane binding, impaired the clearance of α-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of α-synuclein was re-established, aggregation was reduced, and motor phenotypes in Drosophila were alleviated. Altogether, our study demonstrates glycation constitutes a novel drug target that can be explored in synucleinopathies as well as in other neurodegenerative conditions.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationHugo Vicente Miranda, Éva M. Szegő, Luís M. A. Oliveira, Carlo Breda, Ekrem Darendelioglu, Rita M. de Oliveira, Diana G. Ferreira, Marcos A. Gomes, Ruth Rott, Márcia Oliveira, Francesca Munari, Francisco J. Enguita, Tânia Simões, Eva F. Rodrigues, Michael Heinrich, Ivo C. Martins, Irina Zamolo, Olaf Riess, Carlos Cordeiro, Ana Ponces-Freire, Hilal A. Lashuel, Nuno C. Santos, Luisa V. Lopes, Wei Xiang, Thomas M. Jovin, Deborah Penque, Simone Engelender, Markus Zweckstetter, Jochen Klucken, Flaviano Giorgini, Alexandre Quintas, Tiago F. Outeiro; Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies, Brain, Volume 140, Issue 5, 1 May 2017, Pages 1399–1419, https://doi.org/10.1093/brain/awx056pt_PT
dc.identifier.doi10.1093/brain/awx056pt_PT
dc.identifier.issn1460-2156
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/10400.26/19438
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.relationMECANISMO MOLECULAR DE AGREGAÇÃO DA ALFA-SINUCLEÍNA E SUAS VARIANTES NA DOENÇA DE PARKINSON: DESENVOLVI- MENTO DE NOVAS ESTRATÉGIAS TERAPÊUTICAS
dc.relationDECIPHERING THE ROLE SIRT2 IN PARKINSON DISEASE
dc.relationFrom phosphorylation to cleavage: switching on alpha-synuclein aggregation and toxicity
dc.relationToward an understanding of protein glycation in Parkinson's disease: in vitro and in vivo studies of folding, aggregation and degradation pathways of alpha-synuclein, synphilin-1 and parkin under glycation conditions.
dc.relation.publisherversionhttps://doi.org/10.1093/brain/awx056pt_PT
dc.subjectGlycationpt_PT
dc.subjectParkinson’s diseasept_PT
dc.subjectNeurodegenerationpt_PT
dc.subjectAlpha-synucleinpt_PT
dc.titleGlycation potentiates α-synuclein-associated neurodegeneration in synucleinopathiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleMECANISMO MOLECULAR DE AGREGAÇÃO DA ALFA-SINUCLEÍNA E SUAS VARIANTES NA DOENÇA DE PARKINSON: DESENVOLVI- MENTO DE NOVAS ESTRATÉGIAS TERAPÊUTICAS
oaire.awardTitleDECIPHERING THE ROLE SIRT2 IN PARKINSON DISEASE
oaire.awardTitleFrom phosphorylation to cleavage: switching on alpha-synuclein aggregation and toxicity
oaire.awardTitleToward an understanding of protein glycation in Parkinson's disease: in vitro and in vivo studies of folding, aggregation and degradation pathways of alpha-synuclein, synphilin-1 and parkin under glycation conditions.
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F64702%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F23604%2F2005/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F41416%2F2007/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F74287%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-NEU%2F105215%2F2008/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI%2F73430%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-ENB%2F117013%2F2010/PT
oaire.citation.endPage1419pt_PT
oaire.citation.startPage1399pt_PT
oaire.citation.titleBrainpt_PT
oaire.citation.volume140(5)pt_PT
oaire.fundingStreamSFRH
oaire.fundingStreamSFRH
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
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project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
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project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctPolítica de copyright do editorpt_PT
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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