In situ architecture of neuronal α-Synuclein inclusions

• Published in: Nature communications Vol. 12; no. 1; p. 2110
• Main Authors: Trinkaus, Victoria A., Riera-Tur, Irene, Martínez-Sánchez, Antonio, Bäuerlein, Felix J. B., Guo, Qiang, Arzberger, Thomas, Baumeister, Wolfgang, Dudanova, Irina, Hipp, Mark S., Hartl, F. Ulrich, Fernández-Busnadiego, Rubén
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14-04-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/51; 14/19; 14/28; 14/35; 631/378/1689/1718; 631/45/535; 631/535/1258/1260; 64; 64/60; Aggregates; alpha-Synuclein - chemistry; alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Brain - metabolism; Clustering; Cryoelectron Microscopy; Fibrils; Humanities and Social Sciences; Humans; Inclusion Bodies - chemistry; Inclusion Bodies - metabolism; Inclusions; Medical imaging; Membranes; Molecular structure; multidisciplinary; Multiple System Atrophy - genetics; Multiple System Atrophy - metabolism; Neurodegenerative diseases; Neurons - chemistry; Neurons - metabolism; Organelles; Science; Science (multidisciplinary); Synuclein; Tomography
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-22108-0

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.
The molecular architecture of α-Synuclein (α-Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. Here, authors use cryo-electron tomography to image neuronal α-Syn inclusions in situ and find that inclusions consist of α-Syn fibrils intermixed with cellular organelles without interacting directly.