In situ architecture of neuronal alpha-Synuclein inclusions

Trinkaus, Victoria A.; Riera-Tur, Irene; Martinez-Sanchez, Antonio; Bauerlein, Felix J. B.; Guo, Qiang; Arzberger, Thomas; Baumeister, Wolfgang; Dudanova, Irina; Hipp, Mark S.; Hartl, F. Ulrich und Fernandez-Busnadiego, Ruben (2021): In situ architecture of neuronal alpha-Synuclein inclusions. In: Nature Communications, Bd. 12, Nr. 1, 2110

Abstract

The molecular architecture of alpha -Synuclein (alpha -Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. alpha -Syn inclusions were long thought to consist mainly of alpha -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 alpha -Syn inclusions in situ at molecular resolution. We show that inclusions seeded by alpha -Syn aggregates produced recombinantly or purified from patient brain consist of alpha -Syn fibrils crisscrossing a variety of cellular organelles. Using gold-labeled seeds, we find that aggregate seeding is predominantly mediated by small alpha -Syn fibrils, from which cytoplasmic fibrils grow unidirectionally. Detailed analysis of membrane interactions revealed that alpha -Syn fibrils do not contact membranes directly, and that alpha -Syn does not drive membrane clustering. Altogether, we conclusively demonstrate that neuronal alpha -Syn inclusions consist of alpha -Syn fibrils intermixed with membranous organelles, and illuminate the mechanism of aggregate seeding and cellular interaction. The molecular architecture of alpha -Synuclein (alpha -Syn) inclusions, pathognomonic of various neurodegenerative disorders, remains unclear. Here, authors use cryo-electron tomography to image neuronal alpha -Syn inclusions in situ and find that inclusions consist of alpha -Syn fibrils intermixed with cellular organelles without interacting directly.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198