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Identification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregation

dc.contributor.authorPopova, Blagovesta
dc.contributor.authorWang, Dan
dc.contributor.authorRajavel, Abirami
dc.contributor.authorDhamotharan, Karthikeyan
dc.contributor.authorLázaro, Diana F.
dc.contributor.authorGerke, Jennifer
dc.contributor.authorUhrig, Joachim F.
dc.contributor.authorHoppert, Michael
dc.contributor.authorOuteiro, Tiago F.
dc.contributor.authorBraus, Gerhard H.
dc.date.accessioned2021-06-24T12:05:34Z
dc.date.available2021-06-24T12:05:34Z
dc.date.issued2021de
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/17845
dc.description.abstractAggregation 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.de
dc.description.sponsorshipOpen-Access-Publikationsfonds 2021
dc.language.isoengde
dc.rightsopenAccess
dc.rightsNamensnennung 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectα-synuclein; Parkinson’s disease; protein aggregation; oligomerization; peptide drug discovery; yeast,library screeningde
dc.subject.ddc570
dc.titleIdentification of Two Novel Peptides That Inhibit α-Synuclein Toxicity and Aggregationde
dc.typejournalArticlede
dc.identifier.doi10.3389/fnmol.2021.659926
dc.identifier.doi10.3389/fnmol.2021.659926.s001
dc.identifier.doi10.3389/fnmol.2021.659926.s002
dc.identifier.doi10.3389/fnmol.2021.659926.s003
dc.identifier.doi10.3389/fnmol.2021.659926.s004
dc.identifier.doi10.3389/fnmol.2021.659926.s005
dc.identifier.doi10.3389/fnmol.2021.659926.s006
dc.identifier.doi10.3389/fnmol.2021.659926.s007
dc.type.versionpublishedVersionde
dc.relation.eISSN1662-5099
dc.bibliographicCitation.volume14de
dc.type.subtypejournalArticle
dc.bibliographicCitation.articlenumber659926de
dc.description.statuspeerReviewedde
dc.bibliographicCitation.journalFrontiers in Molecular Neurosciencede


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