Outeiro, Tiago Fleming

[["dc.bibliographiccitation.artnumber","128"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Acta Neuropathologica Communications"],["dc.bibliographiccitation.volume","4"],["dc.contributor.author","Lázaro, Diana F."],["dc.contributor.author","Dias, Mariana C."],["dc.contributor.author","Carija, Anita"],["dc.contributor.author","Navarro, Susanna"],["dc.contributor.author","Madaleno, Carolina S."],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Ventura, Salvador"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2019-07-09T11:42:53Z"],["dc.date.available","2019-07-09T11:42:53Z"],["dc.date.issued","2016"],["dc.description.abstract","Abstract α-synuclein (aSyn) is associated with both sporadic and familial forms of Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease. In particular, multiplications and point mutations in the gene encoding for aSyn cause familial forms of PD. Moreover, the accumulation of aSyn in Lewy Bodies and Lewy neurites in disorders such as PD, dementia with Lewy bodies, or multiple system atrophy, suggests aSyn misfolding and aggregation plays an important role in these disorders, collectively known as synucleinopathies. The exact function of aSyn remains unclear, but it is known to be associated with vesicles and membranes, and to have an impact on important cellular functions such as intracellular trafficking and protein degradation systems, leading to cellular pathologies that can be readily studied in cell-based models. Thus, understanding the molecular effects of aSyn point mutations may provide important insight into the molecular mechanisms underlying disease onset. We investigated the effect of the recently identified A53E aSyn mutation. Combining in vitro studies with studies in cell models, we found that this mutation reduces aSyn aggregation and increases proteasome activity, altering normal proteostasis. We observed that, in our experimental paradigms, the A53E mutation affects specific steps of the aggregation process of aSyn and different cellular processes, providing novel ideas about the molecular mechanisms involved in synucleinopathies."],["dc.identifier.doi","10.1186/s40478-016-0402-8"],["dc.identifier.pmid","27938414"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13938"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58777"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.publisher","BioMed Central"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The effects of the novel A53E alpha-synuclein mutation on its oligomerization and aggregation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3949"],["dc.bibliographiccitation.issue","20"],["dc.bibliographiccitation.journal","Lab on a Chip"],["dc.bibliographiccitation.lastpage","3957"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Fernandes, Joao Tiago S."],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Gameiro, Andreia"],["dc.contributor.author","Chu, Virginia"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Conde, Joao P."],["dc.date.accessioned","2018-11-07T09:33:29Z"],["dc.date.available","2018-11-07T09:33:29Z"],["dc.date.issued","2014"],["dc.description.abstract","Parkinson's disease (PD) is a common age-associated neurodegenerative disorder. The protein a-synuclein (aSyn) is a key factor in PD both due to its association with familial and sporadic cases and because it is the main component of the pathological protein aggregates known as Lewy bodies. However, the precise cellular effects of aSyn aggregation are still elusive. Here, we developed an elastomeric microftuldic device equipped with a chemical gradient generator and 9 chambers containing cell traps to study aSyn production and aggregation in Saccharomyces cerevisiae. This study involved capturing single cells, exposing them to specific chemical environments and imaging the expression of aSyn by means of a GFP fusion (aSyn-GFP). Using a galactose (GAL) gradient we modulated aSyn expression and, surprisingly, by tracking the behavior of single cells, we found that the response of individual cells in a population to a given stimulus can differ widely. To study the combined effect of environmental factors and aSyn expression levels, we exposed cells to a gradient of FeCl3. We found a dramatic increase in the percentage of cells displaying aSyn inclusions from 27% to 96%. Finally, we studied the effects of ascorbic acid, an antioxidant, on aSyn aggregation and found a significant reduction in the percentage of cells bearing aSyn inclusions from 87% to 37%. In summary, the device developed here offers a powerful way of studying aSyn biology with single-cell resolution and high throughput using genetically modified yeast cells."],["dc.identifier.doi","10.1039/c4lc00756e"],["dc.identifier.isi","000342866400006"],["dc.identifier.pmid","25167219"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11724"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/31972"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Royal Soc Chemistry"],["dc.relation.issn","1473-0189"],["dc.relation.issn","1473-0197"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Modulation of alpha-synuclein toxicity in yeast using a novel microfluidic-based gradient generator"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","262"],["dc.bibliographiccitation.issue","8"],["dc.bibliographiccitation.journal","Microbial Cell"],["dc.bibliographiccitation.lastpage","279"],["dc.bibliographiccitation.volume","2"],["dc.contributor.author","Menezes, Regina"],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Macedo, Diana"],["dc.contributor.author","Santos, Claudia"],["dc.contributor.author","Outeiro, Tiago"],["dc.date.accessioned","2019-07-09T11:42:42Z"],["dc.date.available","2019-07-09T11:42:42Z"],["dc.date.issued","2015"],["dc.description.abstract","The baker’s yeast Saccharomyces cerevisiae has been extensively explored for our understanding of fundamental cell biology processes highly conserved in the eukaryotic kingdom. In this context, they have proven invaluable in the study of complex mechanisms such as those involved in a variety of human disorders. Here, we first provide a brief historical perspective on the emergence of yeast as an experimental model and on how the field evolved to exploit the potential of the model for tackling the intricacies of various human diseases. In particular, we focus on existing yeast models of the molecular underpinnings of Parkinson’s disease (PD), focusing primarily on the central role of protein quality control systems. Finally, we compile and discuss the major discoveries derived from these studies, highlighting their far-reaching impact on the elucidation of PD-associated mechanisms as well as in the identification of candidate therapeutic targets and compounds with therapeutic potential."],["dc.identifier.doi","10.15698/mic2015.08.219"],["dc.identifier.fs","618425"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13655"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/58730"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","info:eu-repo/grantAgreement/EC/FP7/613793/EU//BACHBERRY"],["dc.relation.euproject","BacHBerry"],["dc.relation.issn","2311-2638"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","From the baker to the bedside: yeast models of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1350"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Zondler, L."],["dc.contributor.author","Miller-Fleming, Leonor"],["dc.contributor.author","Repici, Mariaelena"],["dc.contributor.author","Goncalves, Susana A."],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Rosado-Ramos, Rita"],["dc.contributor.author","Betzer, C."],["dc.contributor.author","Straatman, Kornelis R."],["dc.contributor.author","Jensen, P. H."],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:37:57Z"],["dc.date.available","2018-11-07T09:37:57Z"],["dc.date.issued","2014"],["dc.description.abstract","Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by the loss of neurons in the substantia nigra pars compacta and the presence of Lewy bodies in surviving neurons. These intracellular protein inclusions are primarily composed of misfolded alpha-synuclein (aSyn), which has also been genetically linked to familial and sporadic forms of PD. DJ-1 is a small ubiquitously expressed protein implicated in several pathways associated with PD pathogenesis. Although mutations in the gene encoding DJ-1 lead to familial early-onset PD, the exact mechanisms responsible for its role in PD pathogenesis are still elusive. Previous work has found that DJ-1 - which has protein chaperone-like activity - modulates aSyn aggregation. Here, we investigated possible physical interactions between aSyn and DJ-1 and any consequent functional and pathological relevance. We found that DJ-1 interacts directly with aSyn monomers and oligomers in vitro, and that this also occurs in living cells. Notably, several PD-causing mutations in DJ-1 constrain this interaction. In addition, we found that overexpression of DJ-1 reduces aSyn dimerization, whereas mutant forms of DJ-1 impair this process. Finally, we found that human DJ-1 as well as yeast orthologs of DJ-1 reversed aSyn-dependent cellular toxicity in Saccharomyces cerevisiae. Taken together, these data suggest that direct interactions between DJ-1 and aSyn constitute the basis for a neuroprotective mechanism and that familial mutations in DJ-1 may contribute to PD by disrupting these interactions."],["dc.identifier.doi","10.1038/cddis.2014.307"],["dc.identifier.isi","000341639300041"],["dc.identifier.pmid","25058424"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12113"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/32956"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2041-4889"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","DJ-1 interactions with alpha-synuclein attenuate aggregation and cellular toxicity in models of Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","8"],["dc.contributor.author","Macedo, Diana"],["dc.contributor.author","Jardim, Carolina"],["dc.contributor.author","Figueira, Inês"],["dc.contributor.author","Almeida, A. Filipa"],["dc.contributor.author","McDougall, Gordon J."],["dc.contributor.author","Stewart, Derek"],["dc.contributor.author","Yuste, Jose E."],["dc.contributor.author","Tomás-Barberán, Francisco A."],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Santos, Cláudia N."],["dc.date.accessioned","2020-12-10T18:10:10Z"],["dc.date.available","2020-12-10T18:10:10Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1038/s41598-018-25118-z"],["dc.identifier.eissn","2045-2322"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15433"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/73874"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.notes.intern","Merged from goescholar"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","(Poly)phenol-digested metabolites modulate alpha-synuclein toxicity by regulating proteostasis"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","42"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","7"],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Eckermann, Katrin"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:40:15Z"],["dc.date.available","2018-11-07T09:40:15Z"],["dc.date.issued","2014"],["dc.description.abstract","Protein misfolding and aggregation is a common hallmark in neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), and fronto-temporal dementia (FTD). In these disorders, the misfolding and aggregation of specific proteins occurs alongside neuronal degeneration in somewhat specific brain areas, depending on the disorder and the stage of the disease. However, we still do not fully understand the mechanisms governing protein aggregation, and whether this constitutes a protective or detrimental process. In PD, alpha-synuclein (aSyn) forms protein aggregates, known as Lewy bodies, and is phosphorylated at serine 129. Other residues have also been shown to be phosphorylated, but the significance of phosphorylation in the biology and pathophysiology of the protein is still controversial. In AD and in FTD, hyperphosphorylation of tau protein causes its misfolding and aggregation. Again, our understanding of the precise consequences of tau phosphorylation in the biology and pathophysiology of the protein is still limited. Through the use of a variety of model organisms and technical approaches, we are now gaining stronger insight into the effects of phosphorylation in the behavior of these proteins. In this review, we cover recent findings in the field and discuss how targeting phosphorylation events might be used for therapeutic intervention in these devastating diseases of the nervous system."],["dc.identifier.doi","10.3389/fnmol.2014.00042"],["dc.identifier.isi","000347970100003"],["dc.identifier.pmid","24860424"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11796"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33469"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.relation.eissn","1662-5099"],["dc.relation.issn","1662-5099"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Protein phosphorylation in neurodegeneration: friend or foe?"],["dc.type","review"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1004302"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","PLoS Genetics"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Reimao-Pinto, Madalena M."],["dc.contributor.author","Antas, Pedro"],["dc.contributor.author","Rino, Jose"],["dc.contributor.author","Wawrzycka, Donata"],["dc.contributor.author","Macedo, Diana"],["dc.contributor.author","Rosado-Ramos, Rita"],["dc.contributor.author","Amen, Triana"],["dc.contributor.author","Waiss, Meytal"],["dc.contributor.author","Magalhaes, Filipa"],["dc.contributor.author","Gomes, Andreia"],["dc.contributor.author","Santos, Claudia N."],["dc.contributor.author","Kaganovich, Daniel"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T09:40:35Z"],["dc.date.available","2018-11-07T09:40:35Z"],["dc.date.issued","2014"],["dc.description.abstract","Alpha-synuclein (aSyn) is the main component of proteinaceous inclusions known as Lewy bodies (LBs), the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Although aSyn is phosphorylated at low levels under physiological conditions, it is estimated that similar to 90% of aSyn in LBs is phosphorylated at S129 (pS129). Nevertheless, the significance of pS129 in the biology of aSyn and in PD pathogenesis is still controversial. Here, we harnessed the power of budding yeast in order to assess the implications of phosphorylation on aSyn cytotoxicity, aggregation and sub-cellular distribution. We found that aSyn is phosphorylated on S129 by endogenous kinases. Interestingly, phosphorylation reduced aSyn toxicity and the percentage of cells with cytosolic inclusions, in comparison to cells expressing mutant forms of aSyn (S129A or S129G) that mimic the unphosphorylated form of aSyn. Using high-resolution 4D imaging and fluorescence recovery after photobleaching (FRAP) in live cells, we compared the dynamics of WT and S129A mutant aSyn. While WT aSyn inclusions were very homogeneous, inclusions formed by S129A aSyn were larger and showed FRAP heterogeneity. Upon blockade of aSyn expression, cells were able to clear the inclusions formed by WT aSyn. However, this process was much slower for the inclusions formed by S129A aSyn. Interestingly, whereas the accumulation of WT aSyn led to a marked induction of autophagy, cells expressing the S129A mutant failed to activate this protein quality control pathway. The finding that the phosphorylation state of aSyn on S129 can alter the ability of cells to clear aSyn inclusions provides important insight into the role that this posttranslational modification may have in the pathogenesis of PD and other synucleinopathies, opening novel avenues for investigating the molecular basis of these disorders and for the development of therapeutic strategies."],["dc.identifier.doi","10.1371/journal.pgen.1004302"],["dc.identifier.isi","000337145100008"],["dc.identifier.pmid","24810576"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10122"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/33541"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.issn","1553-7404"],["dc.relation.issn","1553-7390"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Phosphorylation Modulates Clearance of Alpha-Synuclein Inclusions in a Yeast Model of Parkinson's Disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]