Browsing by Subject "Structural biology"

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    In situ architecture of neuronal α-Synuclein inclusions
    (Nature Research, ) Trinkaus, Victoria A.; Riera-Tur, Irene; Martínez Sánchez, Antonio; Bauerlein, Felix J.B.; Guo, Qiang; Arzberger, Thomas; Baumeister, Wolfgang; Dudanova, Irina; Hipp, Mark S.; Ulrich Hartl, F.; Fernández-Busnadiego, Rubén; Ingeniería de la Información y las Comunicaciones
    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.