Outeiro, Tiago Fleming

[["dc.bibliographiccitation.firstpage","3124"],["dc.bibliographiccitation.issue","5"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","3135"],["dc.bibliographiccitation.volume","53"],["dc.contributor.author","Guerreiro, P. S."],["dc.contributor.author","Gerhardt, E."],["dc.contributor.author","Da Fonseca, T. L."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Outeiro, T. F."],["dc.contributor.author","Eckermann, Katrin"],["dc.date.accessioned","2017-09-07T11:44:49Z"],["dc.date.available","2017-09-07T11:44:49Z"],["dc.date.issued","2016"],["dc.description.abstract","Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known as the most frequent cause of familial Parkinson's disease (PD), but are also present in sporadic cases. The G2019S-LRRK2 mutation is located in the kinase domain of the protein, and has consistently been reported to promote a gain of kinase function. Several proteins have been reported as LRRK2 substrates and/or interactors, suggesting possible pathways involved in neurodegeneration in PD. Hyperphosphorylated Tau protein accumulates in neurofibrillary tangles, a typical pathological hallmark in Alzheimer's disease and frontotemporal dementia. In addition, it is also frequently found in the brains of PD patients. Although LRRK2 is a kinase, it appears that a putative interaction with Tau is phosphorylation-independent. However, the underlying mechanisms and the cellular consequences of this interaction are still unclear. In this study, we demonstrate an interaction between LRRK2 and Tau and that LRRK2 promotes the accumulation of non-monomeric and high-molecular weight (HMW) Tau species independent of its kinase activity. Interestingly, we found that LRRK2 increases Tau secretion, possibly as a consequence of an impairment of Tau proteasomal degradation. Our data highlight a mechanism through which LRRK2 regulates intracellular Tau levels, contributing to the progression of the pathology caused by the LRRK2-mediated proteasome impairment. In total, our findings suggest that the interplay between LRRK2 and proteasome activity might constitute a valid target for therapeutic intervention in PD."],["dc.identifier.doi","10.1007/s12035-015-9209-z"],["dc.identifier.gro","3141658"],["dc.identifier.isi","000377935400034"],["dc.identifier.pmid","26014385"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/6231"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1559-1182"],["dc.relation.issn","0893-7648"],["dc.subject","LRRK2; Tau Protein accumulation; Protein degradation"],["dc.title","LRRK2 Promotes Tau Accumulation, Aggregation and Release"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","e1994"],["dc.bibliographiccitation.journal","Cell Death and Disease"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Oliveira, Luis M. A."],["dc.contributor.author","Falomir-Lockhart, Lisandro J."],["dc.contributor.author","Botelho, Michelle Gralle"],["dc.contributor.author","Lin, K-H"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Koch, Jan Christoph"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Taschenberger, Holger"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Lingor, Paul"],["dc.contributor.author","Schuele, B."],["dc.contributor.author","Arndt-Jovin, Donna J."],["dc.contributor.author","Jovin, Thomas M."],["dc.date.accessioned","2018-11-07T09:49:15Z"],["dc.date.available","2018-11-07T09:49:15Z"],["dc.date.issued","2015"],["dc.description.abstract","We have assessed the impact of alpha-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of alpha-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction."],["dc.identifier.doi","10.1038/cddis.2015.318"],["dc.identifier.isi","000367155300027"],["dc.identifier.pmid","26610207"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/12755"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/35470"],["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 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Elevated alpha-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem 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","e0157852"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLoS ONE"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Guedes, Leonor C."],["dc.contributor.author","Soreq, Lilach"],["dc.contributor.author","Lobo, Patricia P."],["dc.contributor.author","Mestre, Tiago"],["dc.contributor.author","Coelho, Miguel"],["dc.contributor.author","Rosa, Mario M."],["dc.contributor.author","Goncalves, Nilza"],["dc.contributor.author","Wales, Pauline"],["dc.contributor.author","Mendes, Tiago"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Fahlbusch, Christiane"],["dc.contributor.author","Bonifati, Vincenzo"],["dc.contributor.author","Bonin, Michael"],["dc.contributor.author","Miltenberger-Miltenyi, Gabriel"],["dc.contributor.author","Borovecki, Fran"],["dc.contributor.author","Soreq, Hermona"],["dc.contributor.author","Ferreira, Joaquim J."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:12:42Z"],["dc.date.available","2018-11-07T10:12:42Z"],["dc.date.issued","2016"],["dc.description.abstract","The prognosis of neurodegenerative disorders is clinically challenging due to the inexistence of established biomarkers for predicting disease progression. Here, we performed an exploratory cross-sectional, case-control study aimed at determining whether gene expression differences in peripheral blood may be used as a signature of Parkinson's disease (PD) progression, thereby shedding light into potential molecular mechanisms underlying disease development. We compared transcriptional profiles in the blood from 34 PD patients who developed postural instability within ten years with those of 33 patients who did not develop postural instability within this time frame. Our study identified >200 differentially expressed genes between the two groups. The expression of several of the genes identified was previously found deregulated in animal models of PD and in PD patients. Relevant genes were selected for validation by real-time PCR in a subset of patients. The genes validated were linked to nucleic acid metabolism, mitochondria, immune response and intracellular-transport. Interestingly, we also found deregulation of these genes in a dopaminergic cell model of PD, a simple paradigm that can now be used to further dissect the role of these molecular players on dopaminergic cell loss. Altogether, our study provides preliminary evidence that expression changes in specific groups of genes and pathways, detected in peripheral blood samples, may be correlated with differential PD progression. Our exploratory study suggests that peripheral gene expression profiling may prove valuable for assisting in prediction of PD prognosis, and identifies novel culprits possibly involved in dopaminergic cell death. Given the exploratory nature of our study, further investigations using independent, well-characterized cohorts will be essential in order to validate our candidates as predictors of PD prognosis and to definitively confirm the value of gene expression analysis in aiding patient stratification and therapeutic intervention."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1371/journal.pone.0157852"],["dc.identifier.isi","000378212000048"],["dc.identifier.pmid","27322389"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13385"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/40290"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Public Library Science"],["dc.relation.haserratum","/handle/2/102958"],["dc.relation.issn","1932-6203"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles"],["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","90"],["dc.bibliographiccitation.issue","1-2"],["dc.bibliographiccitation.journal","Journal of the Neurological Sciences"],["dc.bibliographiccitation.lastpage","95"],["dc.bibliographiccitation.volume","310"],["dc.contributor.author","Szego, Eva M."],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Kermer, Pawel"],["dc.date.accessioned","2018-11-07T08:49:51Z"],["dc.date.available","2018-11-07T08:49:51Z"],["dc.date.issued","2011"],["dc.description.abstract","Cognitive dysfunction can be common among Parkinson's disease (PD) patients, and multiplication of the gene alpha-synuclein (alpha syn) increases the risk of dementia. Here, we studied the role of dopamine-depletion and increased asyn load and aggregation on cholinergic structures in vivo. Wild-type (WT) and mice with A30P asyn overexpression were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MFTP), and the number of cholinergic cells in their nucleus basalis magnocellularis-substantia innominata (NBM-SI), their cortical fiber density and their expression of different genes 1 day or 90 days after the last MPTP-injection were measured. Long-term dopamine depletion decreased the expression of choline acetyl transferase (ChAT) in the NBM-SI of WT mice, but no neuron loss was observed. In contrast, cortical cholinergic fiber density was decreased three months after MPTP-injection. Increased brain-derived neurotrophic factor expression could maintain cholinergic functions under these conditions. Expression of A30P alpha syn in six-months-old transgenic mice resulted in decreased tyrosine receptor kinase B expression, and lower cortical cholinergic fiber density. Dopamine-depletion by MPTP induced cholinergic cell loss in the NBM-SI and increased cortical fiber loss. Our findings may explain why cholinergic cells are more vulnerable in PD, leading to an increased probability of dementia. (C) 2011 Elsevier B.V. All rights reserved."],["dc.identifier.doi","10.1016/j.jns.2011.06.048"],["dc.identifier.isi","000296927500023"],["dc.identifier.pmid","21774947"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/21555"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Elsevier Science Bv"],["dc.publisher.place","Amsterdam"],["dc.relation.eventlocation","Barcelona, SPAIN"],["dc.relation.issn","0022-510X"],["dc.title","Dopamine-depletion and increased alpha-synuclein load induce degeneration of cortical cholinergic fibers in mice"],["dc.type","conference_paper"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","79"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Acta Neuropathologica Communications"],["dc.bibliographiccitation.volume","6"],["dc.contributor.author","Masaracchia, Caterina"],["dc.contributor.author","Hnida, Marilena"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Lopes da Fonseca, Tomás"],["dc.contributor.author","Villar-Pique, Anna"],["dc.contributor.author","Branco, Tiago"],["dc.contributor.author","Stahlberg, Markus A."],["dc.contributor.author","Dean, Camin"],["dc.contributor.author","Fernández, Claudio O."],["dc.contributor.author","Milošević, Ira"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2019-07-09T11:45:45Z"],["dc.date.available","2019-07-09T11:45:45Z"],["dc.date.issued","2018"],["dc.description.abstract","Abstract Alpha-synuclein (aSyn) plays a crucial role in Parkinson\\’s disease (PD) and other synucleinopathies, since it misfolds and accumulates in typical proteinaceous inclusions. While the function of aSyn is thought to be related to vesicle binding and trafficking, the precise molecular mechanisms linking aSyn with synucleinopathies are still obscure. aSyn can spread in a prion-like manner between interconnected neurons, contributing to the propagation of the pathology and to the progressive nature of synucleinopathies. Here, we investigated the interaction of aSyn with membranes and trafficking machinery pathways using cellular models of PD that are amenable to detailed molecular analyses. We found that different species of aSyn can enter cells and form high molecular weight species, and that membrane binding properties are important for the internalization of aSyn. Once internalized, aSyn accumulates in intracellular inclusions. Interestingly, we found that internalization is blocked in the presence of dynamin inhibitors (blocked membrane scission), suggesting the involvement of the endocytic pathway in the internalization of aSyn. By screening a pool of small Rab-GTPase proteins (Rabs) which regulate membrane trafficking, we found that internalized aSyn partially colocalized with Rab5A and Rab7. Initially, aSyn accumulated in Rab4A-labelled vesicles and, at later stages, it reached the autophagy-lysosomal pathway (ALP) where it gets degraded. In total, our study emphasizes the importance of membrane binding, not only as part of the normal function but also as an important step in the internalization and subsequent accumulation of aSyn. Importantly, we identified a fundamental role for Rab proteins in the modulation of aSyn processing, clearance and spreading, suggesting that targeting Rab proteins may hold important therapeutic value in PD and other synucleinopathies."],["dc.identifier.doi","10.1186/s40478-018-0578-1"],["dc.identifier.pmid","30107856"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15309"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/59304"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/98"],["dc.identifier.url","https://sfb1286.uni-goettingen.de/literature/publications/36"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P02: Charakterisierung der ER-Mitochondrien-Kontakte und ihre Rolle in der Signalweiterleitung"],["dc.relation","SFB 1286: Quantitative Synaptologie"],["dc.relation","SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration"],["dc.relation.workinggroup","RG Milosevic (Synaptic Vesicle Dynamics)"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Membrane binding, internalization, and sorting of alpha-synuclein in the cell"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","104721"],["dc.bibliographiccitation.journal","Journal of Proteomics"],["dc.bibliographiccitation.volume","269"],["dc.contributor.author","Brás, Inês C."],["dc.contributor.author","Khani, Mohammad H."],["dc.contributor.author","Riedel, Dietmar"],["dc.contributor.author","Parfentev, Iwan"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","van Riesen, Christoph"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Gollisch, Tim"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2022-10-04T10:21:29Z"],["dc.date.available","2022-10-04T10:21:29Z"],["dc.date.issued","2022"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100001659 Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100004939 Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100007601 Horizon 2020"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100000781 European Research Council"],["dc.identifier.doi","10.1016/j.jprot.2022.104721"],["dc.identifier.pii","S1874391922002457"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114423"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.issn","1874-3919"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","Ectosomes and exosomes modulate neuronal spontaneous activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","5269"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Molecular Neurobiology"],["dc.bibliographiccitation.lastpage","5281"],["dc.bibliographiccitation.volume","55"],["dc.contributor.author","Brasil, Aline A."],["dc.contributor.author","Magalhães, Rayne S. S."],["dc.contributor.author","De Carvalho, Mariana D. C."],["dc.contributor.author","Paiva, Isabel"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Pereira, Marcos D."],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Eleutherio, Elis C. A."],["dc.date.accessioned","2020-12-10T14:14:25Z"],["dc.date.available","2020-12-10T14:14:25Z"],["dc.date.issued","2017"],["dc.identifier.doi","10.1007/s12035-017-0755-4"],["dc.identifier.eissn","1559-1182"],["dc.identifier.issn","0893-7648"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15568"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/71345"],["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","Implications of fALS Mutations on Sod1 Function and Oligomerization in Cell Models"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","25991"],["dc.bibliographiccitation.issue","51"],["dc.bibliographiccitation.journal","Proceedings of the National Academy of Sciences of the United States of America"],["dc.bibliographiccitation.lastpage","26000"],["dc.bibliographiccitation.volume","116"],["dc.contributor.author","Brasil, Aline de Araújo"],["dc.contributor.author","de Carvalho, Mariana Dias Castela"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Queiroz, Daniela Dias"],["dc.contributor.author","Pereira, Marcos Dias"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Eleutherio, Elis Cristina Araujo"],["dc.date.accessioned","2020-04-02T15:01:54Z"],["dc.date.available","2020-04-02T15:01:54Z"],["dc.date.issued","2019"],["dc.description.abstract","Mutations in Cu/Zn superoxide dismutase (Sod1) have been reported in both familial and sporadic amyotrophic lateral sclerosis (ALS). In this study, we investigated the behavior of heteromeric combinations of wild-type (WT) and mutant Sod1 proteins A4V, L38V, G93A, and G93C in human cells. We showed that both WT and mutant Sod1 formed dimers and oligomers, but only mutant Sod1 accumulated in intracellular inclusions. Coexpression of WT and hSod1 mutants resulted in the formation of a larger number of intracellular inclusions per cell than that observed in cells coexpressing WT or mutant hSod1. The number of inclusions was greater in cells expressing A4V hSod1. To eliminate the contribution of endogenous Sod1, and better evaluate the effect of ALS-associated mutant Sod1 expression, we expressed human Sod1 WT and mutants in human cells knocked down for endogenous Sod1 (Sod1-KD), and in sod1Δ yeast cells. Using Sod1-KD cells we found that the WT-A4V heteromers formed higher molecular weight species compared with A4V and WT homomers. Using the yeast model, in conditions of chronological aging, we concluded that cells expressing Sod1 heterodimers showed decreased antioxidant activity, increased oxidative damage, reduced longevity, and oxidative stress-induced mutant Sod1 aggregation. In addition, we also found that ALS-associated Sod1 mutations reduced nuclear localization and, consequently, impaired the antioxidant response, suggesting this change in localization may contribute to disease in familial ALS. Overall, our study provides insight into the molecular underpinnings of ALS and may open avenues for the design of future therapeutic strategies."],["dc.identifier.doi","10.1073/pnas.1902483116"],["dc.identifier.pmid","31796595"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/63570"],["dc.language.iso","en"],["dc.relation.eissn","1091-6490"],["dc.relation.issn","0027-8424"],["dc.relation.issn","1091-6490"],["dc.title","Characterization of the activity, aggregation, and toxicity of heterodimers of WT and ALS-associated mutant Sod1"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","1"],["dc.bibliographiccitation.journal","Journal of Parkinson's Disease"],["dc.bibliographiccitation.lastpage","26"],["dc.contributor.author","Brás, Inês C."],["dc.contributor.author","Khani, Mohammad H."],["dc.contributor.author","Vasili, Eftychia"],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Riedel, Dietmar"],["dc.contributor.author","Parfentev, Iwan"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Fahlbusch, Christiane"],["dc.contributor.author","Urlaub, Henning"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2022-11-01T10:17:15Z"],["dc.date.available","2022-11-01T10:17:15Z"],["dc.date.issued","2022"],["dc.description.abstract","Background: Various cellular pathways have been implicated in the transfer of disease-related proteins between cells, contributing to disease progression and neurodegeneration. However, the overall effects of protein transfer are still unclear. Objective: Here, we performed a systematic comparison of basic molecular mechanisms involved in the release of alpha-synuclein, Tau, and huntingtin, and evaluated functional effects upon internalization by receiving cells. Methods: Evaluation of protein release to the extracellular space in a free form and in extracellular vesicles using an optimized ultracentrifugation protocol. The extracellular effects of the proteins and extracellular vesicles in primary neuronal cultures were assessed using multi-channel electrophysiological recordings combined with a customized spike sorting framework. Results: We demonstrate cells differentially release free-forms of each protein to the extracellular space. Importantly, neuronal activity is distinctly modulated upon protein internalization in primary cortical cultures. In addition, these disease-related proteins also occur in extracellular vesicles, and are enriched in ectosomes. Internalization of ectosomes and exosomes by primary microglial or astrocytic cells elicits the production of pro-inflammatory cytokines, and modifies spontaneous electrical activity in neurons. Objective: Overall, our study demonstrates that released proteins can have detrimental effects for surrounding cells, and suggests protein release pathways may be exploited as therapeutic targets in different neurodegenerative diseases."],["dc.identifier.doi","10.3233/JPD-223516"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/116767"],["dc.notes.intern","DOI-Import GROB-605"],["dc.relation.eissn","1877-718X"],["dc.relation.issn","1877-7171"],["dc.title","Molecular Mechanisms Mediating the Transfer of Disease-Associated Proteins and Effects on Neuronal Activity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","E6506"],["dc.bibliographiccitation.issue","42"],["dc.bibliographiccitation.journal","PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA"],["dc.bibliographiccitation.lastpage","E6515"],["dc.bibliographiccitation.volume","113"],["dc.contributor.author","Villar-Pique, Anna"],["dc.contributor.author","da Fonseca, Tomas Lopes"],["dc.contributor.author","Sant'Anna, Ricardo"],["dc.contributor.author","Szegoe, Eva Monika"],["dc.contributor.author","Fonseca-Ornelas, Luis"],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Carija, Anita"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Masaracchia, Caterina"],["dc.contributor.author","Gonzalez, Enrique Abad"],["dc.contributor.author","Rossetti, Giulia"],["dc.contributor.author","Carloni, Paolo"],["dc.contributor.author","Fernandez, Claudio O."],["dc.contributor.author","Foguel, Debora"],["dc.contributor.author","Milosevic, Ira"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Ventura, Salvador"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-11-07T10:06:57Z"],["dc.date.available","2018-11-07T10:06:57Z"],["dc.date.issued","2016"],["dc.description.abstract","Synucleinopathies are a group of progressive disorders characterized by the abnormal aggregation and accumulation of alpha-synuclein (aSyn), an abundant neuronal protein that can adopt different conformations and biological properties. Recently, aSyn pathology was shown to spread between neurons in a prion-like manner. Proteins like aSyn that exhibit self-propagating capacity appear to be able to adopt different stable conformational states, known as protein strains, which can be modulated both by environmental and by protein-intrinsic factors. Here, we analyzed these factors and found that the unique combination of the neurodegeneration-related metal copper and the pathological H50Q aSyn mutation induces a significant alteration in the aggregation properties of aSyn. We compared the aggregation of WT and H50Q aSyn with and without copper, and assessed the effects of the resultant protein species when applied to primary neuronal cultures. The presence of copper induces the formation of structurally different and less-damaging aSyn aggregates. Interestingly, these aggregates exhibit a stronger capacity to induce aSyn inclusion formation in recipient cells, which demonstrates that the structural features of aSyn species determine their effect in neuronal cells and supports a lack of correlation between toxicity and inclusion formation. In total, our study provides strong support in favor of the hypothesis that protein aggregation is not a primary cause of cytotoxicity."],["dc.identifier.doi","10.1073/pnas.1606791113"],["dc.identifier.isi","000385610400024"],["dc.identifier.pmid","27708160"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/39195"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","Najko"],["dc.publisher","Natl Acad Sciences"],["dc.relation.issn","0027-8424"],["dc.title","Environmental and genetic factors support the dissociation between alpha-synuclein aggregation and toxicity"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.status","published"],["dspace.entity.type","Publication"]]