Publication: In situ architecture of neuronal α-Synuclein inclusions
Authors
Trinkaus, Victoria A. ; Riera-Tur, Irene ; Martínez Sánchez, Antonio ; Bauerlein, Felix J.B. ; Guo, Qiang ; Arzberger, Thomas ; Baumeister, Wolfgang ; Dudanova, Irina ; Hipp, Mark S. ; Ulrich Hartl, F. ; Fernández-Busnadiego, Rubén
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Publisher
Nature Research
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DOI
https://doi.org/10.1038/s41467-021-22108-0
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info:eu-repo/semantics/article
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
Abstract
The 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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Citation
Nature Communications (2021) 12:2110
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