In situ architecture of neuronal α-Synuclein inclusions

Victoria A. Trinkaus, Irene Riera-Tur, Antonio Martínez-Sánchez, Felix J. B. Bäuerlein, Qiang Guo, Thomas Arzberger, Wolfgang Baumeister, Irina Dudanova, Mark S. Hipp, F. Ulrich Hartl, Rubén Fernández-Busnadiego

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    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.
    Original languageEnglish
    Article number2110
    Number of pages10
    JournalNature Communications
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 14-Apr-2021

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