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 () and Rubén Fernández-Busnadiego ()
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Victoria A. Trinkaus: Max Planck Institute of Biochemistry
Irene Riera-Tur: Max Planck Institute of Neurobiology
Antonio Martínez-Sánchez: Max Planck Institute of Biochemistry
Felix J. B. Bäuerlein: Max Planck Institute of Biochemistry
Qiang Guo: Max Planck Institute of Biochemistry
Thomas Arzberger: Munich Cluster for Systems Neurology (SyNergy)
Wolfgang Baumeister: Max Planck Institute of Biochemistry
Irina Dudanova: Max Planck Institute of Neurobiology
Mark S. Hipp: Max Planck Institute of Biochemistry
F. Ulrich Hartl: Max Planck Institute of Biochemistry
Rubén Fernández-Busnadiego: Max Planck Institute of Biochemistry

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22108-0

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