Outeiro, Tiago Fleming

[["dc.bibliographiccitation.firstpage","1270"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","Current drug targets"],["dc.bibliographiccitation.lastpage","80"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Pais, Teresa F."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2019-07-10T08:13:31Z"],["dc.date.available","2019-07-10T08:13:31Z"],["dc.date.issued","2010-10-01"],["dc.description.abstract","Aging has been a subject of interest since primordial times. More recently, it became clear that aging is the major known risk factor for several neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease and Huntington's disease. A major focus in the field of aging is to examine whether the genetic regulators of lifespan also regulate the trigger and/or progression of age-related disorders. Sirtuins, which belong to the Sir2 family of NAD(+)-dependent deacetylases, are known to regulate longevity in yeast, worms, and flies. In mammals, there are seven homologs of the yeast Sir2, Sirt1-7. Therefore, the challenge now is to unravel howthe seven mammalian Sir2 proteins communicate to regulate the cross talk between aging and the onset and progression of age-related disorders. Here, we review how sirtuins contribute for aging and, in particular, for neurodegeneration and how they are becoming attractive targets for therapeutic intervention."],["dc.identifier.fs","577015"],["dc.identifier.pmid","20840069"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6055"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/61267"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1873-5592"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.subject.mesh","Aging"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Disease Progression"],["dc.subject.mesh","Drug Delivery Systems"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Neurodegenerative Diseases"],["dc.subject.mesh","Risk Factors"],["dc.subject.mesh","Sirtuins"],["dc.title","Sirtuins: common targets in aging and in neurodegeneration."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","643"],["dc.bibliographiccitation.issue","11"],["dc.bibliographiccitation.journal","Trends in biochemical sciences"],["dc.bibliographiccitation.lastpage","51"],["dc.bibliographiccitation.volume","35"],["dc.contributor.author","Gonçalves, Susana A."],["dc.contributor.author","Matos, Joana E."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2019-07-09T11:52:51Z"],["dc.date.available","2019-07-09T11:52:51Z"],["dc.date.issued","2010-11-01"],["dc.description.abstract","Several neurodegenerative diseases are characterized by the accumulation of misfolded and aggregated proteins, which lead to neurotoxicity. However, the nature of those toxic species is controversial. Developments in optical microscopy and live-cell imaging are essential in providing crucial insight into the molecular mechanisms involved. In particular, the technique of bimolecular fluorescence complementation (BiFC) represents a remarkable improvement for observing protein-protein interactions within living cells. Unlike other techniques, BiFC provides spatial and temporal resolution and can be carried out in a physiological environment. Among other applications, BiFC has been used to study molecular determinants of oligomerization in neurodegenerative disorders, thereby promising to unveil novel targets for therapeutics. We review the applicability of BiFC for investigating the molecular basis of neurodegenerative diseases associated with protein misfolding and aggregation."],["dc.identifier.doi","10.1016/j.tibs.2010.05.007"],["dc.identifier.fs","576699"],["dc.identifier.pmid","20561791"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6054"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60292"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","0968-0004"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.subject.mesh","Animals"],["dc.subject.mesh","Humans"],["dc.subject.mesh","Luminescent Proteins"],["dc.subject.mesh","Neurons"],["dc.subject.mesh","Protein Binding"],["dc.subject.mesh","Protein Folding"],["dc.subject.mesh","Protein Multimerization"],["dc.subject.mesh","Proteins"],["dc.title","Zooming into protein oligomerization in neurodegeneration using BiFC."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1867"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","3"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Putcha, Preeti"],["dc.contributor.author","Tetzlaff, Julie E."],["dc.contributor.author","Spoelgen, Robert"],["dc.contributor.author","Koker, Mirjam"],["dc.contributor.author","Carvalho, Filipe"],["dc.contributor.author","Hyman, Bradley T."],["dc.contributor.author","McLean, Pamela J."],["dc.date.accessioned","2019-07-09T11:52:50Z"],["dc.date.available","2019-07-09T11:52:50Z"],["dc.date.issued","2008"],["dc.description.abstract","Background: Misfolding, oligomerization, and fibrillization of α-synuclein are thought to be central events in the onset and progression of Parkinson's disease (PD) and related disorders. Although fibrillar α-synuclein is a major component of Lewy bodies (LBs), recent data implicate prefibrillar, oligomeric intermediates as the toxic species. However, to date, oligomeric species have not been identified in living cells. Methodology/Principal Findings Here we used bimolecular fluorescence complementation (BiFC) to directly visualize α-synuclein oligomerization in living cells, allowing us to study the initial events leading to α-synuclein oligomerization, the precursor to aggregate formation. This novel assay provides us with a tool with which to investigate how manipulations affecting α-synuclein aggregation affect the process over time. Stabilization of α-synuclein oligomers via BiFC results in increased cytotoxicity, which can be rescued by Hsp70 in a process that reduces the formation of α-synuclein oligomers. Introduction of PD-associated mutations in α-synuclein did not affect oligomer formation but the biochemical properties of the mutant α-synuclein oligomers differ from those of wild type α-synuclein. Conclusions/Significance This novel application of the BiFC assay to the study of the molecular basis of neurodegenerative disorders enabled the direct visualization of α-synuclein oligomeric species in living cells and its modulation by Hsp70, constituting a novel important tool in the search for therapeutics for synucleinopathies."],["dc.identifier.doi","10.1371/journal.pone.0001867"],["dc.identifier.pmid","18382657"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6053"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60291"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.subject.ddc","610"],["dc.title","Formation of Toxic Oligomeric α-Synuclein Species in Living Cells"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","410"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","419"],["dc.bibliographiccitation.volume","286"],["dc.contributor.author","Tauber, E."],["dc.contributor.author","Miller-Fleming, L."],["dc.contributor.author","Mason, R. P."],["dc.contributor.author","Kwan, W."],["dc.contributor.author","Clapp, J."],["dc.contributor.author","Butler, N. J."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Muchowski, P. J."],["dc.contributor.author","Giorgini, F."],["dc.date.accessioned","2011-04-06T16:14:39Z"],["dc.date.accessioned","2021-10-27T13:22:34Z"],["dc.date.available","2011-04-06T16:14:39Z"],["dc.date.available","2021-10-27T13:22:34Z"],["dc.date.issued","2010"],["dc.description.abstract","Huntington disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the huntingtin (htt) protein. To uncover candidate therapeutic targets and networks involved in pathogenesis, we integrated gene expression profiling and functional genetic screening to identify genes critical for mutant htt toxicity in yeast. Using mRNA profiling, we have identified genes differentially expressed in wild-type yeast in response to mutant htt toxicity as well as in three toxicity suppressor strains: bna4Δ, mbf1Δ, and ume1Δ. BNA4 encodes the yeast homolog of kynurenine 3-monooxygenase, a promising drug target for HD. Intriguingly, despite playing diverse cellular roles, these three suppressors share common differentially expressed genes involved in stress response, translation elongation, and mitochondrial transport. We then systematically tested the ability of the differentially expressed genes to suppress mutant htt toxicity when overexpressed and have thereby identified 12 novel suppressors, including genes that play a role in stress response, Golgi to endosome transport, and rRNA processing. Integrating the mRNA profiling data and the genetic screening data, we have generated a robust network that shows enrichment in genes involved in rRNA processing and ribosome biogenesis. Strikingly, these observations implicate dysfunction of translation in the pathology of HD. Recent work has shown that regulation of translation is critical for life span extension in Drosophila and that manipulation of this process is protective in Parkinson disease models. In total, these observations suggest that pharmacological manipulation of translation may have therapeutic value in HD."],["dc.identifier.doi","10.1074/jbc.M110.101527"],["dc.identifier.pmid","21044956"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6057"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/92107"],["dc.language.iso","en"],["dc.notes.intern","Migrated from goescholar"],["dc.relation.orgunit","Universitätsmedizin Göttingen"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.subject.ddc","610"],["dc.title","Functional Gene Expression Profiling in Yeast Implicates Translational Dysfunction in Mutant Huntingtin Toxicity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e13700"],["dc.bibliographiccitation.issue","10"],["dc.bibliographiccitation.journal","PLoS One"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Büttner, Sabrina"],["dc.contributor.author","Delay, Charlotte"],["dc.contributor.author","Franssens, Vanessa"],["dc.contributor.author","Bammens, Tine"],["dc.contributor.author","Ruli, Doris"],["dc.contributor.author","Zaunschirm, Sandra"],["dc.contributor.author","de Oliveira, Rita Machado"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Madeo, Frank"],["dc.contributor.author","Buée, Luc"],["dc.contributor.author","Galas, Marie-Christine"],["dc.contributor.author","Winderickx, Joris"],["dc.date.accessioned","2019-07-09T11:52:51Z"],["dc.date.available","2019-07-09T11:52:51Z"],["dc.date.issued","2010"],["dc.description.abstract","BACKGROUND: Parkinson's disease is characterized by the presence of cytoplasmic inclusions, known as Lewy bodies, containing both aggregated α-synuclein and its interaction partner, synphilin-1. While synphilin-1 is known to accelerate inclusion formation by α-synuclein in mammalian cells, its effect on cytotoxicity remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: We expressed wild-type synphilin-1 or its R621C mutant either alone or in combination with α-synuclein in the yeast Saccharomyces cerevisiae and monitored the intracellular localization and inclusion formation of the proteins as well as the repercussions on growth, oxidative stress and cell death. We found that wild-type and mutant synphilin-1 formed inclusions and accelerated inclusion formation by α-synuclein in yeast cells, the latter being correlated to enhanced phosphorylation of serine-129. Synphilin-1 inclusions co-localized with lipid droplets and endomembranes. Consistently, we found that wild-type and mutant synphilin-1 interacts with detergent-resistant membrane domains, known as lipid rafts. The expression of synphilin-1 did not incite a marked growth defect in exponential cultures, which is likely due to the formation of aggresomes and the retrograde transport of inclusions from the daughter cells back to the mother cells. However, when the cultures approached stationary phase and during subsequent ageing of the yeast cells, both wild-type and mutant synphilin-1 reduced survival and triggered apoptotic and necrotic cell death, albeit to a different extent. Most interestingly, synphilin-1 did not trigger cytotoxicity in ageing cells lacking the sirtuin Sir2. This indicates that the expression of synphilin-1 in wild-type cells causes the deregulation of Sir2-dependent processes, such as the maintenance of the autophagic flux in response to nutrient starvation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that wild-type and mutant synphilin-1 are lipid raft interacting proteins that form inclusions and accelerate inclusion formation of α-synuclein when expressed in yeast. Synphilin-1 thereby induces cytotoxicity, an effect most pronounced for the wild-type protein and mediated via Sir2-dependent processes."],["dc.identifier.doi","10.1371/journal.pone.0013700"],["dc.identifier.fs","576695"],["dc.identifier.pmid","21060871"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/6056"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/60293"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 2.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/2.0"],["dc.subject.ddc","610"],["dc.subject.mesh","Carrier Proteins"],["dc.subject.mesh","Cell Death"],["dc.subject.mesh","Nerve Tissue Proteins"],["dc.subject.mesh","Phosphorylation"],["dc.subject.mesh","Saccharomyces cerevisiae"],["dc.subject.mesh","Stress, Physiological"],["dc.subject.mesh","alpha-Synuclein"],["dc.title","Synphilin-1 enhances α-synuclein aggregation in yeast and contributes to cellular stress and cell death in a Sir2-dependent manner."],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]