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α‐Synuclein toxicity in yeast and human cells is caused by cell cycle re‐entry and autophagy degradation of ribonucleotide reductase 1

dc.contributor.authorSampaio‐Marques, Belém
dc.contributor.authorGuedes, Ana
dc.contributor.authorVasilevskiy, Igor
dc.contributor.authorGonçalves, Susana
dc.contributor.authorOuteiro, Tiago F.
dc.contributor.authorWinderickx, Joris
dc.contributor.authorBurhans, William C.
dc.contributor.authorLudovico, Paula
dc.date.accessioned2019-11-27T10:13:28Z
dc.date.available2019-11-27T10:13:28Z
dc.date.issued2019de
dc.relation.ISSNAging Cellde
dc.identifier.urihttp://resolver.sub.uni-goettingen.de/purl?gs-1/16742
dc.description.abstractƒ¿ ]Synuclein (aSyn) toxicity is associated with cell cycle alterations, activation of DNA damage responses (DDR), and deregulation of autophagy. However, the relationships between these phenomena remain largely unknown. Here, we demonstrate that in a yeast model of aSyn toxicity and aging, aSyn expression induces Ras2 ]dependent growth signaling, cell cycle re ]entry, DDR activation, autophagy, and autophagic degradation of ribonucleotide reductase 1 (Rnr1), a protein required for the activity of ribonucleotide reductase and dNTP synthesis. These events lead to cell death and aging, which are abrogated by deleting RAS2, inhibiting DDR or autophagy, or overexpressing RNR1. aSyn expression in human H4 neuroglioma cells also induces cell cycle re ]entry and S ]phase arrest, autophagy, and degradation of RRM1, the human homologue of RNR1, and inhibiting autophagic degradation of RRM1 rescues cells from cell death. Our findings represent a model for aSyn toxicity that has important implications for understanding synucleinopathies and other age ]related neurodegenerative diseases.de
dc.language.isoengde
dc.rightsopenAccess
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectalpha‐synuclein; autophagy; cell cycle re‐entry; chronological aging; DNA damage responses; ribonuclease reductasede
dc.subject.ddc573
dc.subject.ddc612
dc.titleα‐Synuclein toxicity in yeast and human cells is caused by cell cycle re‐entry and autophagy degradation of ribonucleotide reductase 1de
dc.typejournalArticlede
dc.identifier.doi10.1111/acel.12922
dc.type.versionpublishedVersionde
dc.relation.pISSN1474-9718
dc.relation.eISSN1474-9726
dc.bibliographicCitation.volume18de
dc.bibliographicCitation.issue4de
dc.type.subtypejournalArticle
dc.description.statuspeerReviewedde
dc.bibliographicCitation.journalAging Cellde


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