Matthes, Dirk

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Frieg, Benedikt"],["dc.contributor.author","Antonschmidt, Leif"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Geraets, James A."],["dc.contributor.author","Najbauer, Eszter E."],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","de Groot, Bert L."],["dc.contributor.author","Andreas, Loren B."],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Schröder, Gunnar F."],["dc.date.accessioned","2022-12-01T08:30:50Z"],["dc.date.available","2022-12-01T08:30:50Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\n α-synuclein misfolding and aggregation into fibrils is a common feature of α-synucleinopathies, such as Parkinson’s disease, in which α-synuclein fibrils are a characteristic hallmark of neuronal inclusions called Lewy bodies. Studies on the composition of Lewy bodies extracted postmortem from brain tissue of Parkinson’s patients revealed that lipids and membranous organelles are also a significant component. Interactions between α-synuclein and lipids have been previously identified as relevant for Parkinson’s disease pathology, however molecular insights into their interactions have remained elusive. Here we present cryo-electron microscopy structures of six α-synuclein fibrils in complex with lipids, revealing specific lipid-fibril interactions. We observe that phospholipids promote an alternative protofilament fold, mediate an unusual arrangement of protofilaments, and fill the central cavities of the fibrils. Together with our previous studies, these structures also indicate a mechanism for fibril-induced lipid extraction, which is likely to be involved in the development of α-synucleinopathies. Specifically, one potential mechanism for the cellular toxicity is the disruption of intracellular vesicles mediated by fibrils and oligomers, and therefore the modulation of these interactions may provide a promising strategy for future therapeutic interventions."],["dc.identifier.doi","10.1038/s41467-022-34552-7"],["dc.identifier.pii","34552"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117993"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.eissn","2041-1723"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The 3D structure of lipidic fibrils of α-synuclein"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Nature Communications"],["dc.bibliographiccitation.volume","13"],["dc.contributor.author","Antonschmidt, Leif"],["dc.contributor.author","Matthes, Dirk"],["dc.contributor.author","Dervişoğlu, Rıza"],["dc.contributor.author","Frieg, Benedikt"],["dc.contributor.author","Dienemann, Christian"],["dc.contributor.author","Leonov, Andrei"],["dc.contributor.author","Nimerovsky, Evgeny"],["dc.contributor.author","Sant, Vrinda"],["dc.contributor.author","Ryazanov, Sergey"],["dc.contributor.author","Giese, Armin"],["dc.contributor.author","Andreas, Loren B."],["dc.date.accessioned","2022-10-04T10:21:08Z"],["dc.date.available","2022-10-04T10:21:08Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract\n Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simulations. Our results reveal stable polar interactions between anle138b and backbone moieties inside the tubular cavity of the fibrils. Such cavities are common in other fibril structures as well."],["dc.identifier.doi","10.1038/s41467-022-32797-w"],["dc.identifier.pii","32797"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/114336"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-600"],["dc.relation.eissn","2041-1723"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]