Outeiro, Tiago Fleming

[["dc.bibliographiccitation.firstpage","1399"],["dc.bibliographiccitation.journal","Brain"],["dc.bibliographiccitation.lastpage","1419"],["dc.bibliographiccitation.volume","140"],["dc.contributor.author","Miranda, Hugo Vicente"],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Oliveira, Luis M. A."],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Darendelioglu, Ekrem"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Ferreira, Diana G."],["dc.contributor.author","Gomes, Marcos Antonio"],["dc.contributor.author","Rott, Ruth"],["dc.contributor.author","Oliveira, Marcia"],["dc.contributor.author","Munari, Francesca"],["dc.contributor.author","Enguita, Francisco Javier"],["dc.contributor.author","Simoes, Tania"],["dc.contributor.author","Rodrigues, Eva F."],["dc.contributor.author","Heinrich, Michael"],["dc.contributor.author","Martins, Ivo C."],["dc.contributor.author","Zamolo, Irina"],["dc.contributor.author","Riess, Olaf"],["dc.contributor.author","Cordeiro, Carlos"],["dc.contributor.author","Ponces-Freire, Ana"],["dc.contributor.author","Lashuel, Hilal Ahmed"],["dc.contributor.author","Santos, Nuno C."],["dc.contributor.author","Lopes, Luisa Vaqueiro"],["dc.contributor.author","Xiang, Wei"],["dc.contributor.author","Jovin, Thomas M."],["dc.contributor.author","Penque, Deborah"],["dc.contributor.author","Engelender, Simone"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Klucken, Jochen"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Quintas, Alexandre"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:24:40Z"],["dc.date.available","2018-11-07T10:24:40Z"],["dc.date.issued","2017"],["dc.description.abstract","alpha-Synuclein misfolding and aggregation is a hallmark in Parkinson's disease and in several other neurodegenerative diseases known as synucleinopathies. The toxic properties of alpha-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 alpha-synuclein toxicity in vitro and in vivo, in Drosophila and in mice. Glycation affected primarily the N-terminal region of alpha-synuclein, reducing membrane binding, impaired the clearance of alpha-synuclein, and promoted the accumulation of toxic oligomers that impaired neuronal synaptic transmission. Strikingly, using glycation inhibitors, we demonstrated that normal clearance of alpha-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."],["dc.identifier.doi","10.1093/brain/awx056"],["dc.identifier.isi","000400069900026"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/42703"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Oxford Univ Press"],["dc.relation.haserratum","/handle/2/103764"],["dc.relation.issn","1460-2156"],["dc.relation.issn","0006-8950"],["dc.title","Glycation potentiates alpha-synuclein-associated neurodegeneration in synucleinopathies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Journal of Neurology Neurosurgery & Psychiatry"],["dc.bibliographiccitation.volume","85"],["dc.contributor.author","Vicente Miranda, Hugo"],["dc.contributor.author","Gomes, Marcos Antonio"],["dc.contributor.author","Branco dos Santos, J."],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:36:19Z"],["dc.date.available","2018-11-07T09:36:19Z"],["dc.date.issued","2014"],["dc.format.extent","A11"],["dc.identifier.doi","10.1136/jnnp-2014-309032.36"],["dc.identifier.isi","000361971900037"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32588"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Bmj Publishing Group"],["dc.publisher.place","London"],["dc.relation.eventlocation","Barcelona, SPAIN"],["dc.relation.issn","1468-330X"],["dc.relation.issn","0022-3050"],["dc.title","GLYCATION MODULATES HUNTINGTIN AGGREGATION AND TOXICITY"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2294"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Biomedicines"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Swaih, Aisha M."],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Sathyasaikumar, Korrapati V."],["dc.contributor.author","Allcock, Natalie"],["dc.contributor.author","Collier, Mary E. W."],["dc.contributor.author","Mason, Robert P."],["dc.contributor.author","Feasby, Adam"],["dc.contributor.author","Herrera, Federico"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Schwarcz, Robert"],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2022-10-04T10:21:48Z"],["dc.date.available","2022-10-04T10:21:48Z"],["dc.date.issued","2022"],["dc.description.abstract","The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD)—which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO. In order to test this hypothesis, we employed bimolecular fluorescence complementation (BiFC) and found that KMO physically interacts with soluble HTT exon 1 protein fragment in living cells. Notably, expansion of the disease-causing polyglutamine tract in HTT leads to the formation of proteinaceous intracellular inclusions that disrupt this interaction with KMO, markedly decreasing BiFC efficiency. Using confocal microscopy and ultrastructural analysis, we determined KMO and HTT localisation within the cell and found that the KMO-HTT interaction is localized to the outer mitochondrial membrane. These data suggest that KMO may interact with a pool of HTT at the mitochondrial membrane, highlighting a possible physiological role for mitochondrial HTT. The KMO-HTT interaction is abrogated upon polyglutamine expansion, which may indicate a heretofore unrecognized relevance in the pathogenesis of this disorder."],["dc.identifier.doi","10.3390/biomedicines10092294"],["dc.identifier.pii","biomedicines10092294"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114503"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.eissn","2227-9059"],["dc.title","Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","705"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Journal of Molecular Medicine"],["dc.bibliographiccitation.lastpage","713"],["dc.bibliographiccitation.volume","91"],["dc.contributor.author","Amaral, Marta"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Scrutton, Nigel S."],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2018-11-07T09:24:21Z"],["dc.date.available","2018-11-07T09:24:21Z"],["dc.date.issued","2013"],["dc.description.abstract","Metabolites of the kynurenine pathway (KP), which arise from the degradation of tryptophan, have been studied in detail for over a century and garnered the interest of the neuroscience community in the late 1970s and early 1980s with work uncovering the neuromodulatory potential of this pathway. Much research in the following decades has found that perturbations in the levels of KP metabolites likely contribute to the pathogenesis of several neurodegenerative diseases. More recently, it has become apparent that targeting KP enzymes, in particular kynurenine 3-monooxygenase (KMO), may hold substantial therapeutic potential for these disorders. Here we provide an overview of the KP, the neuroactive properties of KP metabolites and their role in neurodegeneration. We also discuss KMO as a therapeutic target for these disorders, and our recent resolution of the crystallographic structure of KMO, which will permit the development of new and improved KMO inhibitors which may ultimately expedite clinical application of these compounds."],["dc.identifier.doi","10.1007/s00109-013-1046-9"],["dc.identifier.isi","000319297200007"],["dc.identifier.pmid","23636512"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29804"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","0946-2716"],["dc.title","The causative role and therapeutic potential of the kynurenine pathway in neurodegenerative disease"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1141"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Biomedicines"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Jordan, Kate L."],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2022-06-01T09:39:55Z"],["dc.date.available","2022-06-01T09:39:55Z"],["dc.date.issued","2022"],["dc.description.abstract","Rab GTPases (Rabs) are small proteins that play crucial roles in vesicle transport and membrane trafficking. Owing to their widespread functions in several steps of vesicle trafficking, Rabs have been implicated in the pathogenesis of several disorders, including cancer, diabetes, and multiple neurodegenerative diseases. As treatments for neurodegenerative conditions are currently rather limited, the identification and validation of novel therapeutic targets, such as Rabs, is of great importance. This review summarises proof-of-concept studies, demonstrating that modulation of Rab GTPases in the context of Alzheimer’s disease (AD) can ameliorate disease-related phenotypes, and provides an overview of the current state of the art for the pharmacological targeting of Rabs. Finally, we also discuss the barriers and challenges of therapeutically targeting these small proteins in humans, especially in the context of AD."],["dc.identifier.doi","10.3390/biomedicines10051141"],["dc.identifier.pii","biomedicines10051141"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/108596"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-572"],["dc.relation.eissn","2227-9059"],["dc.title","Therapeutic Targeting of Rab GTPases: Relevance for Alzheimer’s Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3763"],["dc.bibliographiccitation.issue","19"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","3775"],["dc.bibliographiccitation.volume","26"],["dc.contributor.author","Branco-Santos, Joana"],["dc.contributor.author","Herrera, Federico"],["dc.contributor.author","Poças, Gonçalo M."],["dc.contributor.author","Pires-Afonso, Yolanda"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Domingos, Pedro M."],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2020-12-10T18:19:15Z"],["dc.date.available","2020-12-10T18:19:15Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1093/hmg/ddx260"],["dc.identifier.eissn","1460-2083"],["dc.identifier.issn","0964-6906"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/75178"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","Protein phosphatase 1 regulates huntingtin exon 1 aggregation and toxicity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","149"],["dc.bibliographiccitation.journal","Neurobiology of Disease"],["dc.bibliographiccitation.lastpage","161"],["dc.bibliographiccitation.volume","70"],["dc.contributor.author","Yin, Guowei"],["dc.contributor.author","Da Fonseca, Tomas Lopes"],["dc.contributor.author","Eisbach, Sibylle E."],["dc.contributor.author","Anduaga, Ane Martin"],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Orcellet, Maria L."],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Guerreiro, Patricia"],["dc.contributor.author","Lazar, Diana F."],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Fernandez, Claudio O."],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Goody, Roger S."],["dc.contributor.author","Itzen, Aymelt"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Zweckstetter, Markus"],["dc.date.accessioned","2017-09-07T11:45:30Z"],["dc.date.available","2017-09-07T11:45:30Z"],["dc.date.issued","2014"],["dc.description.abstract","Alpha-synuclein (alpha S) misfolding is associated with Parkinson's disease (PD) but little is known about the mechanisms underlying alpha S toxicity. Increasing evidence suggests that defects in membrane transport play an important role in neuronal dysfunction. Here we demonstrate that the GTPase Rab8a interacts with alpha S in rodent brain. NMR spectroscopy reveals that the C-terminus of alpha S binds to the functionally important switch region as well as the C-terminal tail of Rab8a. In line with a direct Rab8a/alpha S interaction, Rab8a enhanced alpha S aggregation and reduced alpha S-induced cellular toxicity. In addition, Rab8 - the Drosophila ortholog of Rab8a - ameliorated alpha S-oligomer specific locomotor impairment and neuron loss in fruit flies. In support of the pathogenic relevance of the alpha S-Rab8a interaction, phosphorylation of alpha S at S129 enhanced binding to Rab8a, increased formation of insoluble alpha S aggregates and reduced cellular toxicity. Our study provides novel mechanistic insights into the interplay of the GTPase Rab8a and alpha S cytotoxicity, and underscores the therapeutic potential of targeting this interaction. (C) 2014 Elsevier Inc. All rights reserved."],["dc.identifier.doi","10.1016/j.nbd.2014.06.018"],["dc.identifier.gro","3142046"],["dc.identifier.isi","000340691400015"],["dc.identifier.pmid","24983211"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3945"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1095-953X"],["dc.relation.issn","0969-9961"],["dc.title","alpha-Synuclein interacts with the switch region of Rab8a in a Ser129 phosphorylation-dependent manner"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","755"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","766"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Sajjad, Muhammad U."],["dc.contributor.author","Green, Edward W."],["dc.contributor.author","Miller-Fleming, Leonor"],["dc.contributor.author","Hands, Sarah"],["dc.contributor.author","Herrera, Federico"],["dc.contributor.author","Campesan, Susanna"],["dc.contributor.author","Khoshnan, Ali"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Wyttenbach, Andreas"],["dc.date.accessioned","2018-11-07T09:44:28Z"],["dc.date.available","2018-11-07T09:44:28Z"],["dc.date.issued","2014"],["dc.description.abstract","The oxidation-sensitive chaperone protein DJ-1 has been implicated in several human disorders including cancer and neurodegenerative diseases. During neurodegeneration associated with protein misfolding, such as that observed in Alzheimer's disease and Huntington's disease (HD), both oxidative stress and protein chaperones have been shown to modulate disease pathways. Therefore, we set out to investigate whether DJ-1 plays a role in HD. We found that DJ-1 expression and its oxidation state are abnormally increased in the human HD brain, as well as in mouse and cell models of HD. Furthermore, overexpression of DJ-1 conferred protection in vivo against neurodegeneration in yeast and Drosophila. Importantly, the DJ-1 protein directly interacted with an expanded fragment of huntingtin Exon 1 (httEx1) in test tube experiments and in cell models and accelerated polyglutamine aggregation and toxicity in an oxidation-sensitive manner. Our findings clearly establish DJ-1 as a potential therapeutic target for HD and provide the basis for further studies into the role of DJ-1 in protein misfolding diseases."],["dc.identifier.doi","10.1093/hmg/ddt466"],["dc.identifier.isi","000330841700016"],["dc.identifier.pmid","24070869"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/34400"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1460-2083"],["dc.relation.issn","0964-6906"],["dc.title","DJ-1 modulates aggregation and pathogenesis in models of Huntington's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3129"],["dc.bibliographiccitation.issue","12"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","3137"],["dc.bibliographiccitation.volume","23"],["dc.contributor.author","Vittori, Angelica"],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Repici, Mariaelena"],["dc.contributor.author","Orth, Michael"],["dc.contributor.author","Roos, Raymund A. C."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Hollox, Edward J."],["dc.date.accessioned","2018-11-07T09:38:55Z"],["dc.date.available","2018-11-07T09:38:55Z"],["dc.date.issued","2014"],["dc.description.abstract","Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3-which encodes the neuronal glucose transporter GLUT3-could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1-the Drosophila melanogaster homologue of this glucose transporter-ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for HD."],["dc.identifier.doi","10.1093/hmg/ddu022"],["dc.identifier.isi","000337038600005"],["dc.identifier.pmid","24452335"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33165"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Oxford Univ Press"],["dc.relation.issn","1460-2083"],["dc.relation.issn","0964-6906"],["dc.title","Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Journal of Neurology Neurosurgery & Psychiatry"],["dc.bibliographiccitation.volume","85"],["dc.contributor.author","Branco dos Santos, J."],["dc.contributor.author","Herrera, Federico"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:36:18Z"],["dc.date.available","2018-11-07T09:36:18Z"],["dc.date.issued","2014"],["dc.format.extent","A11"],["dc.identifier.doi","10.1136/jnnp-2014-309032.34"],["dc.identifier.isi","000361971900035"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32586"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Bmj Publishing Group"],["dc.publisher.place","London"],["dc.relation.eventlocation","Barcelona, SPAIN"],["dc.relation.issn","1468-330X"],["dc.relation.issn","0022-3050"],["dc.title","EXPLORING THE ROLE OF PHOSPHORYLATION IN HUNTINGTIN AGGREGATION DYNAMICS"],["dc.type","conference_abstract"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]