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In situ architecture of neuronal α-Synuclein inclusions.

Nat Commun. 2021 Apr 14;12(1):2110. doi: 10.1038/s41467-021-22108-0. PMID: 33854052.

Authors/Editors: Trinkaus VA, Riera-Tur I, Martínez-Sánchez A, Bäuerlein FJB, Guo Q, Arzberger T, Baumeister W, Dudanova I, Hipp MS, Hartl FU, Fernández-Busnadiego R.
Publication Date: 2021



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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