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Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

2017Journal article Restricted access
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dc.contributor.authorMiranda, Hugo Vicente
dc.contributor.authorSzego, 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.authorFreire, Ana Ponces
dc.contributor.authorLashuel, Hilal A.
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.accessioned2018-04-16T13:48:23Z
dc.date.available2018-04-16T13:48:23Z
dc.date.issued2017
dc.description© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.pt_PT
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 conditionspt_PT
dc.description.sponsorshipAuthors were supported by: H.V.M. (Fundação para a Ciência e Tecnologia (FCT), Portugal SFRH/BPD/64702/ 2009 and SFRH/BPD/109347/2015; EU FP7 project MEFOPA), L.M.A.O (FCT - SFRH/BD/23604/2005; CIRM-BMFB joint grant, 315050 AZ0101-31P6855), R.M.O. and T.S. (FCT SFRH/BPD/41416/2007; SFRH/ BPD/31209/2006); W.X. (Deutsche Forschungsgemeinschaft, SFB539/A3); C.B. and F.G. (Parkinson’s UK and the Medical Research Council, UK). S.E. is supported by Israel Academy of Sciences, Rappaport Family Institute for Research in the Medical Sciences, The Allen and Jewel Prince Center for Neurodegenerative Disorders of the Brain. T.F.O. (EMBO Installation Grant; Marie Curie IRG, Neurofold; DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain; I.C.M. (FCT SFRH/BPD/74287/2010; Investigador FCT IF/00772/ 2013). This work was supported by: FCT PTDC/SAUNEU/105215/2008, PTDC/QUI/73430/2006, PTDC/SAUENB/117013/2010, PTDC/NEU-OSD/5644/2014; EU FP7 project MEFOPA; CIRM-BMFB joint grant (315050 AZ0101-31P6855); Max Planck Society; and European Union (NEURASYNC PITNGA-2009-238316).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBrain 2017: 140; 1399–1419pt_PT
dc.identifier.doi10.1093/brain/awx056pt_PT
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/10451/32818
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Presspt_PT
dc.relationSFRH/BPD/64702/ 2009pt_PT
dc.relationTargeting the glycation defenses as a protective strategy for Parkinson’s disease
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.relationDEVELOPMENT OF INHIBITORS OF DENGUE VIRUS ASSEMBLY
dc.relationPTDC/SAUNEU/105215/2008pt_PT
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.relationNEURASYNC PITNGA-2009-238316pt_PT
dc.relation.publisherversionhttps://academic.oup.com/brainpt_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.awardTitleTargeting the glycation defenses as a protective strategy for Parkinson’s disease
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.awardTitleDEVELOPMENT OF INHIBITORS OF DENGUE VIRUS ASSEMBLY
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%2FBPD%2F109347%2F2015/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/PIDDAC/SFRH%2FBPD%2F74287%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FQUI%2F73430%2F2006/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FNEU-OSD%2F5644%2F2014/PT
oaire.citation.endPage1419pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage1399pt_PT
oaire.citation.titleBrainpt_PT
oaire.citation.volume140pt_PT
oaire.fundingStreamPIDDAC
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
project.funder.identifierhttp://doi.org/10.13039/501100001871
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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.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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