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Glycation potentiates α-synuclein-associated neurodegeneration in synucleinopathies

2017-05-01Journal article Restricted access
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dc.contributor.authorVicente Miranda, Hugo
dc.contributor.authorSzego, Éva M.
dc.contributor.authorOliveira, Luís M.A.
dc.contributor.authorBreda, Carlo
dc.contributor.authorDarendelioglu, Ekrem
dc.contributor.authorde Oliveira, Rita M.
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.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.accessioned2018-03-22T17:37:25Z
dc.date.available2018-03-22T17:37:25Z
dc.date.issued2017-05-01
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.sponsorshipAuthors were supported by: H.V.M. (Fundac¸a˜o para a Cieˆncia 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 May 1;140(5):1399-1419. doi: 10.1093/brain/awx056.pt_PT
dc.identifier.doi10.1093/brain/awx056pt_PT
dc.identifier.issn0006-8950
dc.identifier.urihttp://hdl.handle.net/10400.18/5439
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Press/Guarantors of Brainpt_PT
dc.relation.publisherversionhttps://academic.oup.com/brain/article-lookup/doi/10.1093/brain/awx056pt_PT
dc.subjectAgingpt_PT
dc.subjectAnimalspt_PT
dc.subjectCell Differentiationpt_PT
dc.subjectCell Survivalpt_PT
dc.subjectCells, Culturedpt_PT
dc.subjectDisease Models, Animalpt_PT
dc.subjectDrosophilapt_PT
dc.subjectEnzyme Inhibitorspt_PT
dc.subjectFemalept_PT
dc.subjectGlycosylationpt_PT
dc.subjectHippocampuspt_PT
dc.subjectHumanspt_PT
dc.subjectInduced Pluripotent Stem Cellspt_PT
dc.subjectMalept_PT
dc.subjectMicept_PT
dc.subjectMice, Transgenicpt_PT
dc.subjectNeurodegenerative Diseasespt_PT
dc.subjectProtein Aggregation, Pathologicalpt_PT
dc.subjectProtein Processing, Post-Translationalpt_PT
dc.subjectPyruvaldehydept_PT
dc.subjectRatspt_PT
dc.subjectYeastspt_PT
dc.subjectalpha-Synucleinpt_PT
dc.subjectGenómica Funcional e Estruturalpt_PT
dc.titleGlycation potentiates α-synuclein-associated neurodegeneration in synucleinopathiespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage1419pt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPage1399pt_PT
oaire.citation.titleBrainpt_PT
oaire.citation.volume140pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT

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