Popova, Blagovesta

[["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","14"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Wang, Dan"],["dc.contributor.author","Rajavel, Abirami"],["dc.contributor.author","Dhamotharan, Karthikeyan"],["dc.contributor.author","Lázaro, Diana F."],["dc.contributor.author","Gerke, Jennifer"],["dc.contributor.author","Uhrig, Joachim F."],["dc.contributor.author","Hoppert, Michael"],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2021-06-01T09:42:26Z"],["dc.date.available","2021-06-01T09:42:26Z"],["dc.date.issued","2021"],["dc.description.abstract","Aggregation of α-synuclein (αSyn) into proteinaceous deposits is a pathological hallmark of a range of neurodegenerative diseases including Parkinson’s disease (PD). Numerous lines of evidence indicate that the accumulation of toxic oligomeric and prefibrillar αSyn species may underpin the cellular toxicity and spread of pathology between cells. Therefore, aggregation of αSyn is considered a priority target for drug development, as aggregation inhibitors are expected to reduce αSyn toxicity and serve as therapeutic agents. Here, we used the budding yeast S. cerevisiae as a platform for the identification of short peptides that inhibit αSyn aggregation and toxicity. A library consisting of approximately one million peptide variants was utilized in two high-throughput screening approaches for isolation of library representatives that reduce αSyn-associated toxicity and aggregation. Seven peptides were isolated that were able to suppress specifically αSyn toxicity and aggregation in living cells. Expression of the peptides in yeast reduced the accumulation of αSyn-induced reactive oxygen species and increased cell viability. Next, the peptides were chemically synthesized and probed for their ability to modulate αSyn aggregation in vitro . Two synthetic peptides, K84s and K102s, of 25 and 19 amino acids, respectively, significantly inhibited αSyn oligomerization and aggregation at sub-stoichiometric molar ratios. Importantly, K84s reduced αSyn aggregation in human cells. These peptides represent promising αSyn aggregation antagonists for the development of future therapeutic interventions."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3389/fnmol.2021.659926"],["dc.identifier.pmid","33912013"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/17845"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/85254"],["dc.identifier.url","https://mbexc.uni-goettingen.de/literature/publications/420"],["dc.notes.intern","DOI-Import GROB-425"],["dc.notes.intern","Merged from goescholar"],["dc.relation","EXC 2067: Multiscale Bioimaging"],["dc.relation.eissn","1662-5099"],["dc.relation.workinggroup","RG Outeiro (Experimental Neurodegeneration)"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","FEMS Yeast Research"],["dc.bibliographiccitation.volume","18"],["dc.contributor.author","Magalhães, Rayne S S"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Braus, Gerhard H"],["dc.contributor.author","Outeiro, Tiago F"],["dc.contributor.author","Eleutherio, Elis C A"],["dc.date.accessioned","2020-12-10T18:19:12Z"],["dc.date.available","2020-12-10T18:19:12Z"],["dc.date.issued","2018"],["dc.identifier.doi","10.1093/femsyr/foy066"],["dc.identifier.eissn","1567-1364"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/75156"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-354"],["dc.title","The trehalose protective mechanism during thermal stress in Saccharomyces cerevisiae: the roles of Ath1 and Agt1"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e1006098"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","PLOS Genetics"],["dc.bibliographiccitation.volume","12"],["dc.contributor.author","Kleinknecht, Alexandra"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Lázaro, Diana F."],["dc.contributor.author","Pinho, Raquel"],["dc.contributor.author","Valerius, Oliver"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.editor","Lu, Bingwei"],["dc.date.accessioned","2018-09-28T07:41:43Z"],["dc.date.available","2018-09-28T07:41:43Z"],["dc.date.issued","2016"],["dc.description.abstract","Parkinson´s disease (PD) is characterized by the presence of proteinaceous inclusions called Lewy bodies that are mainly composed of α-synuclein (αSyn). Elevated levels of oxidative or nitrative stresses have been implicated in αSyn related toxicity. Phosphorylation of αSyn on serine 129 (S129) modulates autophagic clearance of inclusions and is prominently found in Lewy bodies. The neighboring tyrosine residues Y125, Y133 and Y136 are phosphorylation and nitration sites. Using a yeast model of PD, we found that Y133 is required for protective S129 phosphorylation and for S129-independent proteasome clearance. αSyn can be nitrated and form stable covalent dimers originating from covalent crosslinking of two tyrosine residues. Nitrated tyrosine residues, but not di-tyrosine-crosslinked dimers, contributed to αSyn cytotoxicity and aggregation. Analysis of tyrosine residues involved in nitration and crosslinking revealed that the C-terminus, rather than the N-terminus of αSyn, is modified by nitration and di-tyrosine formation. The nitration level of wild-type αSyn was higher compared to that of A30P mutant that is non-toxic in yeast. A30P formed more dimers than wild-type αSyn, suggesting that dimer formation represents a cellular detoxification pathway in yeast. Deletion of the yeast flavohemoglobin gene YHB1 resulted in an increase of cellular nitrative stress and cytotoxicity leading to enhanced aggregation of A30P αSyn. Yhb1 protected yeast from A30P-induced mitochondrial fragmentation and peroxynitrite-induced nitrative stress. Strikingly, overexpression of neuroglobin, the human homolog of YHB1, protected against αSyn inclusion formation in mammalian cells. In total, our data suggest that C-terminal Y133 plays a major role in αSyn aggregate clearance by supporting the protective S129 phosphorylation for autophagy and by promoting proteasome clearance. C-terminal tyrosine nitration increases pathogenicity and can only be partially detoxified by αSyn di-tyrosine dimers. Our findings uncover a complex interplay between S129 phosphorylation and C-terminal tyrosine modifications of αSyn that likely participates in PD pathology."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2016"],["dc.identifier.doi","10.1371/journal.pgen.1006098"],["dc.identifier.pmid","27341336"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/13384"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15831"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.relation.eissn","1553-7404"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","C-Terminal Tyrosine Residue Modifications Modulate the Protective Phosphorylation of Serine 129 of α-Synuclein in a Yeast Model of Parkinson's Disease"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","27567"],["dc.bibliographiccitation.issue","33"],["dc.bibliographiccitation.journal","The Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","27579"],["dc.bibliographiccitation.volume","287"],["dc.contributor.author","Petroi, Doris"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Taheri-Talesh, Naimeh"],["dc.contributor.author","Irniger, Stefan"],["dc.contributor.author","Shahpasandzadeh, Hedieh"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2018-09-28T08:45:30Z"],["dc.date.available","2018-09-28T08:45:30Z"],["dc.date.issued","2012"],["dc.description.abstract","Parkinson disease is the second most common neurodegenerative disease. The molecular hallmark is the accumulation of proteinaceous inclusions termed Lewy bodies containing misfolded and aggregated α-synuclein. The molecular mechanism of clearance of α-synuclein aggregates was addressed using the bakers' yeast Saccharomyces cerevisiae as the model. Overexpression of wild type α-synuclein or the genetic variant A53T integrated into one genomic locus resulted in a gene copy-dependent manner in cytoplasmic proteinaceous inclusions reminiscent of the pathogenesis of the disease. In contrast, overexpression of the genetic variant A30P resulted only in transient aggregation, whereas the designer mutant A30P/A36P/A76P neither caused aggregation nor impaired yeast growth. The α-synuclein accumulation can be cleared after promoter shut-off by a combination of autophagy and vacuolar protein degradation. Whereas the proteasomal inhibitor MG-132 did not significantly inhibit aggregate clearance, treatment with phenylmethylsulfonyl fluoride, an inhibitor of vacuolar proteases, resulted in significant reduction in clearance. Consistently, a cim3-1 yeast mutant restricted in the 19 S proteasome regulatory subunit was unaffected in clearance, whereas an Δatg1 yeast mutant deficient in autophagy showed a delayed aggregate clearance response. A cim3-1Δatg1 double mutant was still able to clear aggregates, suggesting additional cellular mechanisms for α-synuclein clearance. Our data provide insight into the mechanisms yeast cells use for clearing different species of α-synuclein and demonstrate a higher contribution of the autophagy/vacuole than the proteasome system. This contributes to the understanding of how cells can cope with toxic and/or aggregated proteins and may ultimately enable the development of novel strategies for therapeutic intervention."],["dc.identifier.doi","10.1074/jbc.M112.361865"],["dc.identifier.pmid","22722939"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15838"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1083-351X"],["dc.title","Aggregate clearance of α-synuclein in Saccharomyces cerevisiae depends more on autophagosome and vacuole function than on the proteasome"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","e1009407"],["dc.bibliographiccitation.issue","3"],["dc.bibliographiccitation.journal","PLoS Genetics"],["dc.bibliographiccitation.volume","17"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Wang, Dan"],["dc.contributor.author","Pätz, Christina"],["dc.contributor.author","Akkermann, Dagmar"],["dc.contributor.author","Lázaro, Diana F."],["dc.contributor.author","Galka, Dajana"],["dc.contributor.author","Kolog Gulko, Miriam"],["dc.contributor.author","Bohnsack, Markus T."],["dc.contributor.author","Möbius, Wiebke"],["dc.contributor.author","Bohnsack, Katherine E."],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2021-04-14T08:28:05Z"],["dc.date.available","2021-04-14T08:28:05Z"],["dc.date.issued","2021"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.1371/journal.pgen.1009407"],["dc.identifier.pmid","33657088"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/82500"],["dc.identifier.url","https://sfb1190.med.uni-goettingen.de/production/literature/publications/140"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-399"],["dc.relation","SFB 1190: Transportmaschinen und Kontaktstellen zellulärer Kompartimente"],["dc.relation","SFB 1190 | P04: Der GET-Rezeptor als ein Eingangstor zum ER und sein Zusammenspiel mit GET bodies"],["dc.relation.eissn","1553-7404"],["dc.relation.orgunit","Abteilung Molekulare Mikrobiologie & Genetik"],["dc.relation.workinggroup","RG K. Bohnsack (RNA Metabolism)"],["dc.rights","CC BY 4.0"],["dc.title","DEAD-box RNA helicase Dbp4/DDX10 is an enhancer of α-synuclein toxicity and oligomerization"],["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","e1004741"],["dc.bibliographiccitation.journal","PLoS Genetics"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Lazaro, Diana F."],["dc.contributor.author","Rodrigues, Eva F."],["dc.contributor.author","Langohr, Ramona"],["dc.contributor.author","Shahpasandzadeh, Hedieh"],["dc.contributor.author","Ribeiro, Thales"],["dc.contributor.author","Guerreiro, Patricia"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Kroehnert, Katharina"],["dc.contributor.author","Klucken, Jochen"],["dc.contributor.author","Pereira, Marcos D."],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Kruse, Niels"],["dc.contributor.author","Mollenhauer, Brit"],["dc.contributor.author","Rizzoli, Silvio"],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Danzer, Karin M."],["dc.contributor.author","Outeiro, Tiago F."],["dc.date.accessioned","2017-09-07T11:45:25Z"],["dc.date.available","2017-09-07T11:45:25Z"],["dc.date.issued","2014"],["dc.description.abstract","Aggregation of alpha-synuclein (ASYN) in Lewy bodies and Lewy neurites is the typical pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Furthermore, mutations in the gene encoding for ASYN are associated with familial and sporadic forms of PD, suggesting this protein plays a central role in the disease. However, the precise contribution of ASYN to neuronal dysfunction and death is unclear. There is intense debate about the nature of the toxic species of ASYN and little is known about the molecular determinants of oligomerization and aggregation of ASYN in the cell. In order to clarify the effects of different mutations on the propensity of ASYN to oligomerize and aggregate, we assembled a panel of 19 ASYN variants and compared their behaviour. We found that familial mutants linked to PD (A30P, E46K, H50Q, G51D and A53T) exhibited identical propensities to oligomerize in living cells, but had distinct abilities to form inclusions. While the A30P mutant reduced the percentage of cells with inclusions, the E46K mutant had the opposite effect. Interestingly, artificial proline mutants designed to interfere with the helical structure of the N-terminal domain, showed increased propensity to form oligomeric species rather than inclusions. Moreover, lysine substitution mutants increased oligomerization and altered the pattern of aggregation. Altogether, our data shed light into the molecular effects of ASYN mutations in a cellular context, and established a common ground for the study of genetic and pharmacological modulators of the aggregation process, opening new perspectives for therapeutic intervention in PD and other synucleinopathies."],["dc.identifier.doi","10.1371/journal.pgen.1004741"],["dc.identifier.gro","3142024"],["dc.identifier.isi","000345455200011"],["dc.identifier.pmid","25393002"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/11136"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/3701"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1553-7404"],["dc.relation.issn","1553-7390"],["dc.rights","CC BY 3.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/3.0"],["dc.title","Systematic Comparison of the Effects of Alpha-synuclein Mutations on Its Oligomerization and Aggregation"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","145"],["dc.bibliographiccitation.lastpage","156"],["dc.bibliographiccitation.seriesnr","1948"],["dc.contributor.author","Brás, Inês Caldeira"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.contributor.editor","Bartels, Tim"],["dc.date.accessioned","2021-06-02T10:44:27Z"],["dc.date.available","2021-06-02T10:44:27Z"],["dc.date.issued","2019"],["dc.identifier.doi","10.1007/978-1-4939-9124-2_12"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/87042"],["dc.notes.intern","DOI-Import GROB-425"],["dc.publisher","Springer New York"],["dc.publisher.place","New York, NY"],["dc.relation.crisseries","Methods in Molecular Biology"],["dc.relation.eisbn","978-1-4939-9124-2"],["dc.relation.isbn","978-1-4939-9123-5"],["dc.relation.ispartof","Methods in Molecular Biology"],["dc.relation.ispartof","Alpha-Synuclein : Methods and Protocols"],["dc.relation.ispartofseries","Methods in Molecular Biology; 1948"],["dc.title","Yeast-Based Screens to Target Alpha-Synuclein Toxicity"],["dc.type","book_chapter"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","31224"],["dc.bibliographiccitation.issue","45"],["dc.bibliographiccitation.journal","The Journal of Biological Chemistry"],["dc.bibliographiccitation.lastpage","31240"],["dc.bibliographiccitation.volume","289"],["dc.contributor.author","Shahpasandzadeh, Hedieh"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Kleinknecht, Alexandra"],["dc.contributor.author","Fraser, Paul E."],["dc.contributor.author","Outeiro, Tiago F."],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2018-09-28T08:29:52Z"],["dc.date.available","2018-09-28T08:29:52Z"],["dc.date.issued","2014"],["dc.description.abstract","Parkinson disease is associated with the progressive loss of dopaminergic neurons from the substantia nigra. The pathological hallmark of the disease is the accumulation of intracytoplasmic inclusions known as Lewy bodies that consist mainly of post-translationally modified forms of α-synuclein. Whereas phosphorylation is one of the major modifications of α-synuclein in Lewy bodies, sumoylation has recently been described. The interplay between α-synuclein phosphorylation and sumoylation is poorly understood. Here, we examined the interplay between these modifications as well as their impact on cell growth and inclusion formation in yeast. We found that α-synuclein is sumoylated in vivo at the same sites in yeast as in human cells. Impaired sumoylation resulted in reduced yeast growth combined with an increased number of cells with inclusions, suggesting that this modification plays a protective role. In addition, inhibition of sumoylation prevented autophagy-mediated aggregate clearance. A defect in α-synuclein sumoylation could be suppressed by serine 129 phosphorylation by the human G protein-coupled receptor kinase 5 (GRK5) in yeast. Phosphorylation reduced foci formation, alleviated yeast growth inhibition, and partially rescued autophagic α-synuclein degradation along with the promotion of proteasomal degradation, resulting in aggregate clearance in the absence of a small ubiquitin-like modifier. These findings suggest a complex interplay between sumoylation and phosphorylation in α-synuclein aggregate clearance, which may open new horizons for the development of therapeutic strategies for Parkinson disease."],["dc.identifier.doi","10.1074/jbc.M114.559237"],["dc.identifier.pmid","25231978"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15835"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1083-351X"],["dc.title","Interplay between sumoylation and phosphorylation for protection against α-synuclein inclusions"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","275"],["dc.bibliographiccitation.issue","2"],["dc.bibliographiccitation.journal","Human Molecular Genetics"],["dc.bibliographiccitation.lastpage","290"],["dc.bibliographiccitation.volume","25"],["dc.contributor.author","Tenreiro, Sandra"],["dc.contributor.author","Rosado-Ramos, Rita"],["dc.contributor.author","Gerhardt, Ellen"],["dc.contributor.author","Favretto, Filippo"],["dc.contributor.author","Magalhães, Filipa"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Zweckstetter, Markus"],["dc.contributor.author","Braus, Gerhard H."],["dc.contributor.author","Outeiro, Tiago Fleming"],["dc.date.accessioned","2018-09-28T08:13:48Z"],["dc.date.available","2018-09-28T08:13:48Z"],["dc.date.issued","2016"],["dc.description.abstract","Synucleins belong to a family of intrinsically unstructured proteins that includes alpha-synuclein (aSyn), beta-synuclein (bSyn) and gamma-synuclein (gSyn). aSyn is the most studied member of the synuclein family due to its central role in genetic and sporadic forms of Parkinson's disease and other neurodegenerative disorders known as synucleionopathies. In contrast, bSyn and gSyn have been less studied, but recent reports also suggest that, unexpectedly, these proteins may also cause neurotoxicity. Here, we explored the yeast toolbox to investigate the cellular effects of bSyn and gSyn. We found that bSyn is toxic and forms cytosolic inclusions that are similar to those formed by aSyn. Moreover, we found that bSyn shares similar toxicity mechanisms with aSyn, including vesicular trafficking impairment and induction of oxidative stress. We demonstrate that co-expression of aSyn and bSyn exacerbates cytotoxicity, due to increased dosage of toxic synuclein forms, and that they are able to form heterodimers in both yeast and in human cells. In contrast, gSyn is not toxic and does not form inclusions in yeast cells. Altogether, our findings shed light into the question of whether bSyn can exert toxic effects and confirms the occurrence of aSyn/bSyn heterodimers, opening novel perspectives for the development of novel strategies for therapeutic intervention in synucleinopathies."],["dc.identifier.doi","10.1093/hmg/ddv470"],["dc.identifier.pmid","26586132"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15834"],["dc.language.iso","en"],["dc.notes.status","final"],["dc.relation.eissn","1460-2083"],["dc.title","Yeast reveals similar molecular mechanisms underlying alpha- and beta-synuclein toxicity"],["dc.type","journal_article"],["dc.type.internalPublication","unknown"],["dspace.entity.type","Publication"]]