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.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.firstpage","94"],["dc.bibliographiccitation.journal","Frontiers in Molecular Neuroscience"],["dc.bibliographiccitation.volume","11"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Kleinknecht, Alexandra"],["dc.contributor.author","Arendarski, Patricia"],["dc.contributor.author","Mischke, Jasmin"],["dc.contributor.author","Wang, Dan"],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2018-09-28T07:27:45Z"],["dc.date.available","2018-09-28T07:27:45Z"],["dc.date.issued","2018"],["dc.description.abstract","Aggregation of α-synuclein (αSyn) plays a central role in the pathogenesis of Parkinson's disease (PD). The budding yeast Saccharomyces cerevisiae serves as reference cell to study the interplay between αSyn misfolding, cytotoxicity and post-translational modifications (PTMs). The synuclein family includes α, β and γ isoforms. β-synuclein (βSyn) and αSyn are found at presynaptic terminals and both proteins are presumably involved in disease pathogenesis. Similar to αSyn, expression of βSyn leads to growth deficiency and formation of intracellular aggregates in yeast. Co-expression of αSyn and βSyn exacerbates the cytotoxicity. This suggests an important role of βSyn homeostasis in PD pathology. We show here that the small ubiquitin-like modifier SUMO is an important determinant of protein stability and βSyn-induced toxicity in eukaryotic cells. Downregulation of sumoylation in a yeast strain, defective for the SUMO-encoding gene resulted in reduced yeast growth, whereas upregulation of sumoylation rescued growth of yeast cell expressing βSyn. This corroborates a protective role of the cellular sumoylation machinery against βSyn-induced toxicity. Upregulation of sumoylation significantly reduced βSyn aggregate formation. This is an indirect molecular process, which is not directly linked to βSyn sumoylation because amino acid substitutions in the lysine residues required for βSyn sumoylation decreased aggregation without changing yeast cellular toxicity. αSyn aggregates are more predominantly degraded by the autophagy/vacuole than by the 26S ubiquitin proteasome system. We demonstrate a vice versa situation for βSyn, which is mainly degraded in the 26S proteasome. Downregulation of sumoylation significantly compromised the clearance of βSyn by the 26S proteasome and increased protein stability. This effect is specific, because depletion of functional SUMO did neither affect βSyn aggregate formation nor its degradation by the autophagy/vacuolar pathway. Our data support that cellular βSyn toxicity and aggregation do not correlate in their cellular impact as for αSyn but rather represent two distinct independent molecular functions and molecular mechanisms. These insights into the relationship between βSyn-induced toxicity, aggregate formation and degradation demonstrate a significant distinction between the impact of αSyn compared to βSyn on eukaryotic cells."],["dc.description.sponsorship","Open-Access-Publikationsfonds 2018"],["dc.identifier.doi","10.3389/fnmol.2018.00094"],["dc.identifier.pmid","29636661"],["dc.identifier.pmid","29636661"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/15081"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/15830"],["dc.language.iso","en"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","final"],["dc.publisher","Frontiers Media S.A."],["dc.relation.eissn","1662-5099"],["dc.rights","CC BY 4.0"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Sumoylation Protects Against β-Synuclein Toxicity in Yeast"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","2229"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Cells"],["dc.bibliographiccitation.volume","10"],["dc.contributor.author","Popova, Blagovesta"],["dc.contributor.author","Galka, Dajana"],["dc.contributor.author","Häffner, Nicola"],["dc.contributor.author","Wang, Dan"],["dc.contributor.author","Schmitt, Kerstin"],["dc.contributor.author","Valerius, Oliver"],["dc.contributor.author","Knop, Michael"],["dc.contributor.author","Braus, Gerhard H."],["dc.date.accessioned","2021-10-01T09:58:24Z"],["dc.date.available","2021-10-01T09:58:24Z"],["dc.date.issued","2021"],["dc.description.abstract","Parkinson\\’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity."],["dc.description.abstract","Parkinson’s disease (PD) is the most prevalent movement disorder characterized with loss of dopaminergic neurons in the brain. One of the pathological hallmarks of the disease is accumulation of aggregated α-synuclein (αSyn) in cytoplasmic Lewy body inclusions that indicates significant dysfunction of protein homeostasis in PD. Accumulation is accompanied with highly elevated S129 phosphorylation, suggesting that this posttranslational modification is linked to pathogenicity and altered αSyn inclusion dynamics. To address the role of S129 phosphorylation on protein dynamics further we investigated the wild type and S129A variants using yeast and a tandem fluorescent timer protein reporter approach to monitor protein turnover and stability. Overexpression of both variants leads to inhibited yeast growth. Soluble S129A is more stable and additional Y133F substitution permits αSyn degradation in a phosphorylation-independent manner. Quantitative cellular proteomics revealed significant αSyn-dependent disturbances of the cellular protein homeostasis, which are increased upon S129 phosphorylation. Disturbances are characterized by decreased abundance of the ubiquitin-dependent protein degradation machinery. Biotin proximity labelling revealed that αSyn interacts with the Rpt2 base subunit. Proteasome subunit depletion by reducing the expression of the corresponding genes enhances αSyn toxicity. Our studies demonstrate that turnover of αSyn and depletion of the proteasome pool correlate in a complex relationship between altered proteasome composition and increased αSyn toxicity."],["dc.description.sponsorship","Deutsche Forschungsgemeinschaft"],["dc.description.sponsorship","Open-Access-Publikationsfonds 2021"],["dc.identifier.doi","10.3390/cells10092229"],["dc.identifier.pii","cells10092229"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/90054"],["dc.language.iso","en"],["dc.notes.intern","DOI Import GROB-469"],["dc.relation.eissn","2073-4409"],["dc.relation.orgunit","Abteilung Molekulare Mikrobiologie & Genetik"],["dc.rights","CC BY 4.0"],["dc.title","α-Synuclein Decreases the Abundance of Proteasome Subunits and Alters Ubiquitin Conjugates in Yeast"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.subtype","original_ja"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]