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","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","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","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.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"]]