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In situ architecture of neuronal α-Synuclein inclusions

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dc.archivorevisadoCryoelectron tomography
dc.contributor.authorTrinkaus, Victoria A.
dc.contributor.authorRiera-Tur, Irene
dc.contributor.authorMartínez Sánchez, Antonio
dc.contributor.authorBauerlein, Felix J.B.
dc.contributor.authorGuo, Qiang
dc.contributor.authorArzberger, Thomas
dc.contributor.authorBaumeister, Wolfgang
dc.contributor.authorDudanova, Irina
dc.contributor.authorHipp, Mark S.
dc.contributor.authorUlrich Hartl, F.
dc.contributor.authorFernández-Busnadiego, Rubén
dc.contributor.departmentIngeniería de la Información y las Comunicaciones
dc.date.accessioned2025-01-18T19:33:38Z
dc.date.available2025-01-18T19:33:38Z
dc.description© The Author(s) 2021. This manuscript version is made available under the CC-BY- 4.0 license http://creativecommons.org/licenses/by/4.0/. This document is the Published version of a Published Work that appeared in final form in Nature Communications. To access the final edited and published work see https://doi.org/10.1038/s41467-021-22108-0
dc.description.abstractThe molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. α-Syn inclusions were long thought to consist mainly of α-Syn fibrils, but recent reports pointed to intracellular membranes as the major inclusion component. Here, we use cryo-electron tomography (cryo-ET) to image neuronal α-Syn inclusions in situ at molecular resolution. We show that inclusions seeded by α-Syn aggregates produced recombinantly or purified from patient brain consist of α-Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small α-Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that α-Syn fibrils do not contact membranes directly, and that α-Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal α-Syn inclusions consist of α-Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction.
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dc.format.extent10
dc.identifier.citationNature Communications (2021) 12:2110
dc.identifier.doihttps://doi.org/10.1038/s41467-021-22108-0
dc.identifier.issnElectronic: 2041-1723
dc.identifier.urihttp://hdl.handle.net/10201/148743
dc.languageenges
dc.publisherNature Research
dc.relationV.A.T. was supported by the Graduate School of Quantitative Biosciences Munich. V.A.T., I.R.-T., A.M.-S., F.J.B., Q.G., W.B., I.D., M.S.H., F.U.H., and R.F.-B. have received funding from the European Commission (FP7 GA ERC-2012-SyG_318987-ToPAG). I.D. acknowledges financial support from the Horst Kübler-Stiftung. V.A.T., T.A., M.S.H., F.U.H., and R.F.-B. acknowledge funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through Germany’s Excellence Strategy—EXC 2067/1—390729940 (R.F.-B.) and EXC 2145 – 390857198 (V.A.T., T.A., M.S.H. and F.U.H). F.U.H. and R.F.-B. were funded by the joint efforts of The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative. MJFF administers the grant ASAP-000282 on behalf of ASAP and itself.es
dc.relation.publisherversionhttps://www.nature.com/articles/s41467-021-22108-0
dc.rightsinfo:eu-repo/semantics/openAccesses
dc.rightsAtribución 4.0 Internacional*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectParkinson's disease
dc.subjectStructural biology
dc.titleIn situ architecture of neuronal α-Synuclein inclusionses
dc.typeinfo:eu-repo/semantics/articlees
dspace.entity.typePublicationes
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