Outeiro, Tiago Fleming

[["dc.bibliographiccitation.firstpage","120"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Brain Pathology"],["dc.bibliographiccitation.lastpage","132"],["dc.bibliographiccitation.volume","31"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Bondarevaite, Odeta"],["dc.contributor.author","Adams, Sara"],["dc.contributor.author","Leite, Marta"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Attems, Johannes"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2021-04-14T08:24:10Z"],["dc.date.available","2021-04-14T08:24:10Z"],["dc.date.issued","2020"],["dc.description.abstract","Loss of function mutations within the vesicular trafficking protein Ras analogy in brain 39B (RAB39B) are associated with rare X-linked Parkinson’s disease (PD). Physiologically, RAB39B is localized to Golgi vesicles and recycling endosomes and is required for glutamatergic receptor maturation but also for alpha-Synuclein (aSyn) homeostasis and the inhibition of its aggregation. Despite evidence linking RAB39B to neurodegeneration, the involvement of the protein in idiopathic neurodegenerative diseases remains undetermined. Here, analysis of the spatial distribution and expression of RAB39B was conducted in post-mortem human brain tissue from cases of dementia with Lewy bodies (DLB, n = 10), Alzheimer’s disease (AD, n = 12) and controls (n = 12). Assessment of cortical RAB39B immunoreactivity using tissue microarrays revealed an overall reduction in the area of RAB39B positive gray matter in DLB cases when compared to controls and AD cases. Strikingly, RAB39B co-localized with beta-amyloid (Aβ) plaques in all cases examined and was additionally present in a subpopulation of Lewy bodies (LBs) in DLB. Biochemical measures of total RAB39B levels within the temporal cortex were unchanged between DLB, AD and controls. However, upon subcellular fractionation, a reduction of RAB39B in the cytoplasmic pool was found in DLB cases, alongside an increase of phosphorylated aSyn and Aβ in whole tissue lysates. The reduction of cytoplasmic RAB39B is consistent with an impaired reserve capacity for RAB39B-associated functions, which in turn may facilitate LB aggregation and synaptic impairment. Collectively, our data support the involvement of RAB39B in the pathogenesis of DLB and the co-aggregation of RAB39B with Aβ in plaques suggests that age-associated cerebral Aβ pathology may be contributory to the loss of RAB39B. Thus RAB39B, its associated functional pathways and its entrapment in aggregates may be considered as future targets for therapeutic interventions to impede the overall pathological burden and cellular dysfunction in Lewy body diseases."],["dc.identifier.doi","10.1111/bpa.12890"],["dc.identifier.pmid","32762091"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/81186"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/166"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/97"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.eissn","1750-3639"],["dc.relation.issn","1015-6305"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.title","RAB39B is redistributed in dementia with Lewy bodies and is sequestered within aβ plaques and Lewy bodies"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.journal","Movement Disorders"],["dc.contributor.author","Koss, David J."],["dc.contributor.author","Campesan, Susanna"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2021-06-01T09:42:12Z"],["dc.date.available","2021-06-01T09:42:12Z"],["dc.date.issued","2021"],["dc.description.abstract","Intracellular vesicular trafficking is essential for neuronal development, function, and homeostasis and serves to process, direct, and sort proteins, lipids, and other cargo throughout the cell. This intricate system of membrane trafficking between different compartments is tightly orchestrated by Ras analog in brain (RAB) GTPases and their effectors. Of the 66 members of the RAB family in humans, many have been implicated in neurodegenerative diseases and impairment of their functions contributes to cellular stress, protein aggregation, and death. Critically, RAB39B loss-of-function mutations are known to be associated with X-linked intellectual disability and with rare early-onset Parkinson's disease. Moreover, recent studies have highlighted altered RAB39B expression in idiopathic cases of several Lewy body diseases (LBDs). This review contextualizes the role of RAB proteins in LBDs and highlights the consequences of RAB39B impairment in terms of endosomal trafficking, neurite outgrowth, synaptic maturation, autophagy, as well as alpha-synuclein homeostasis. Additionally, the potential for therapeutic intervention is examined via a discussion of the recent progress towards the development of specific RAB modulators. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society"],["dc.identifier.doi","10.1002/mds.28605"],["dc.identifier.pmid","33939203"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85175"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/271"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/124"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-425"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.eissn","1531-8257"],["dc.relation.issn","0885-3185"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.title","Dysfunction of RAB39B‐ Mediated Vesicular Trafficking in Lewy Body Diseases"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","overview_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","599"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Journal of Molecular Medicine"],["dc.bibliographiccitation.lastpage","611"],["dc.bibliographiccitation.volume","91"],["dc.contributor.author","Repici, Mariaelena"],["dc.contributor.author","Straatman, Kornelis R."],["dc.contributor.author","Balduccio, Nadia"],["dc.contributor.author","Enguita, Francisco Javier"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2018-11-07T09:25:06Z"],["dc.date.available","2018-11-07T09:25:06Z"],["dc.date.issued","2013"],["dc.description.abstract","Mutations in the protein DJ-1 cause recessive forms of early onset familial Parkinson's disease (PD). To date, most of the causative mutations studied destabilize formation of DJ-1 homodimers, which appears to be closely linked to its normal function in oxidative stress and other cellular processes. Despite the importance of understanding the dimerization dynamics of this protein, this aspect of DJ-1 biology has not previously been directly studied in living cells. Here, we use bimolecular fluorescence complementation to study DJ-1 dimerization and find not only that DJ-1 forms homodimers in living cells but that most PD causative DJ-1 mutations disrupt this process, including the L166P, M26I, L10P, and P158a dagger mutations. Interestingly, the E64D mutant form of DJ-1 retains the ability to form homodimers. However, while wild-type DJ-1 dimers are stabilized under oxidative stress conditions, we find that the E64D mutation blocks this stabilization. Furthermore, our data show that the E64D mutation potentiates the formation of aggresomes containing DJ-1. We also observe that while the widely studied L166P mutation prevents DJ-1 from forming homodimers or heterodimers with wild-type protein, the mutant protein is able to partially disrupt formation of wild-type homodimers. In summary, by investigating DJ-1 dimerization in living cells, we have uncovered several novel properties of PD causative mutations in DJ-1, which may ultimately provide novel insight into PD pathogenesis and possible therapeutic options."],["dc.description.sponsorship","Parkinson's UK [G-0902]"],["dc.identifier.doi","10.1007/s00109-012-0976-y"],["dc.identifier.isi","000318690500007"],["dc.identifier.pmid","23183826"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10278"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/29988"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Springer"],["dc.relation.issn","0946-2716"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Parkinson's disease-associated mutations in DJ-1 modulate its dimerization in living cells"],["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.artnumber","e1005995"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","PLoS Genetics"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Goncalves, Susana A."],["dc.contributor.author","Macedo, Diana"],["dc.contributor.author","Raquel, Helena"],["dc.contributor.author","Simoes, Pedro D."],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Ramalho, Jose S."],["dc.contributor.author","Barral, Duarte C."],["dc.contributor.author","Moita, Luis Ferreira"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:16:08Z"],["dc.date.available","2018-11-07T10:16:08Z"],["dc.date.issued","2016"],["dc.description.abstract","Alpha-Synuclein (aSyn) misfolding and aggregation is common in several neurodegenerative diseases, including Parkinson's disease and dementia with Lewy bodies, which are known as synucleinopathies. Accumulating evidence suggests that secretion and cell-to-cell trafficking of pathological forms of aSyn may explain the typical patterns of disease progression. However, the molecular mechanisms controlling aSyn aggregation and spreading of pathology are still elusive. In order to obtain unbiased information about the molecular regulators of aSyn oligomerization, we performed a microscopy-based large-scale RNAi screen in living cells. Interestingly, we identified nine Rab GTPase and kinase genes that modulated aSyn aggregation, toxicity and levels. From those, Rab8b, Rab11a, Rab13 and Slp5 were able to promote the clearance of aSyn inclusions and rescue aSyn induced toxicity. Furthermore, we found that endocytic recycling and secretion of aSyn was enhanced upon Rab11a and Rab13 expression in cells accumulating aSyn inclusions. Overall, our study resulted in the identification of new molecular players involved in the aggregation, toxicity, and secretion of aSyn, opening novel avenues for our understanding of the molecular basis of synucleinopathies."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1371/journal.pgen.1005995"],["dc.identifier.isi","000375231900038"],["dc.identifier.pmid","27123591"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13248"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40974"],["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.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","shRNA-Based Screen Identifies Endocytic Recycling Pathway Components That Act as Genetic Modifiers of Alpha-Synuclein Aggregation, Secretion and Toxicity"],["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","1077"],["dc.bibliographiccitation.issue","4"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","1091"],["dc.bibliographiccitation.volume","24"],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Nugent, Marie L."],["dc.contributor.author","Estranero, Jasper G."],["dc.contributor.author","Kyriacou, Charalambos P."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Steinert, Joern R."],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2018-11-07T10:00:53Z"],["dc.date.available","2018-11-07T10:00:53Z"],["dc.date.issued","2015"],["dc.description.abstract","A central pathological hallmark of Parkinson's disease (PD) is the presence of proteinaceous depositions known as Lewy bodies, which consist largely of the protein alpha-synuclein (aSyn). Mutations, multiplications and polymorphisms in the gene encoding aSyn are associated with familial forms of PD and susceptibility to idiopathic PD. Alterations in aSyn impair neuronal vesicle formation/transport, and likely contribute to PD pathogenesis by neuronal dysfunction and degeneration. a Syn is functionally associated with several Rab family GTPases, which perform various roles in vesicle trafficking. Here, we explore the role of the endosomal recycling factor Rab11 in the pathogenesis of PD using Drosophila models of aSyn toxicity. We find that aSyn induces synaptic potentiation at the larval neuromuscular junction by increasing synaptic vesicle (SV) size, and that these alterations are reversed by Rab11 overexpression. Furthermore, Rab11 decreases aSyn aggregation and ameliorates several aSyn-dependent phenotypes in both larvae and adult fruit flies, including locomotor activity, degeneration of dopaminergic neurons and shortened lifespan. This work emphasizes the importance of Rab11 in the modulation of SV size and consequent enhancement of synaptic function. Our results suggest that targeting Rab11 activity could have a therapeutic value in PD."],["dc.identifier.doi","10.1093/hmg/ddu521"],["dc.identifier.isi","000350138300015"],["dc.identifier.pmid","25305083"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11741"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/37900"],["dc.notes.intern","Merged from goescholar"],["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.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Rab11 modulates alpha-synuclein-mediated defects in synaptic transmission and behaviour"],["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","61"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","77"],["dc.bibliographiccitation.volume","56"],["dc.contributor.author","Repici, Mariaelena"],["dc.contributor.author","Hassanjani, Mahdieh"],["dc.contributor.author","Maddison, Daniel C."],["dc.contributor.author","Garção, Pedro"],["dc.contributor.author","Cimini, Sara"],["dc.contributor.author","Patel, Bhavini"],["dc.contributor.author","Szegö, Éva M."],["dc.contributor.author","Straatman, Kornelis R."],["dc.contributor.author","Lilley, Kathryn S."],["dc.contributor.author","Borsello, Tiziana"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Panman, Lia"],["dc.contributor.author","Giorgini, Flaviano"],["dc.date.accessioned","2020-12-10T14:14:28Z"],["dc.date.available","2020-12-10T14:14:28Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1007/s12035-018-1084-y"],["dc.identifier.eissn","1559-1182"],["dc.identifier.issn","0893-7648"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15569"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71349"],["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","The Parkinson’s Disease-Linked Protein DJ-1 Associates with Cytoplasmic mRNP Granules During Stress and Neurodegeneration"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","36798"],["dc.bibliographiccitation.journal","Scientific Reports"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Vicente Miranda, Hugo"],["dc.contributor.author","Gomes, Marcos Antonio"],["dc.contributor.author","Branco-Santos, Joana"],["dc.contributor.author","Breda, Carlo"],["dc.contributor.author","Lazaro, Diana F."],["dc.contributor.author","Lopes, Lusa Vaqueiro"],["dc.contributor.author","Herrera, Federico"],["dc.contributor.author","Giorgini, Flaviano"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:05:42Z"],["dc.date.available","2018-11-07T10:05:42Z"],["dc.date.issued","2016"],["dc.description.abstract","Protein glycation is an age-dependent posttranslational modification associated with several neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. By modifying aminogroups, glycation interferes with folding of proteins, increasing their aggregation potential. Here, we studied the effect of pharmacological and genetic manipulation of glycation on huntingtin (HTT), the causative protein in Huntington's disease (HD). We observed that glycation increased the aggregation of mutant HTT exon 1 fragments associated with HD (HTT72Q and HTT103Q) in yeast and mammalian cell models. We found that glycation impairs HTT clearance thereby promoting its intracellular accumulation and aggregation. Interestingly, under these conditions autophagy increased and the levels of mutant HTT released to the culture medium decreased. Furthermore, increased glycation enhanced HTT toxicity in human cells and neurodegeneration in fruit flies, impairing eclosion and decreasing life span. Overall, our study provides evidence that glycation modulates HTT exon-1 aggregation and toxicity, and suggests it may constitute a novel target for therapeutic intervention in HD."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1038/srep36798"],["dc.identifier.isi","000388069800001"],["dc.identifier.pmid","27857176"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13956"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/38949"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Nature Publishing Group"],["dc.relation.issn","2045-2322"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Glycation potentiates neurodegeneration in models of Huntington'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.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"]]