In situ architecture of neuronal alpha-Synuclein inclusions
Victoria A Trinkaus,
Felix J.B. Baeuerlein,
Mark S Hipp,
F. Ulrich Hartl,
Posted 07 Aug 2020
bioRxiv DOI: 10.1101/2020.08.07.234138
Posted 07 Aug 2020
Alpha-Synuclein (alpha-Syn) aggregation is a hallmark of devastating neurodegenerative disorders including Parkinsons disease (PD) and multiple systems atrophy (MSA). alpha-Syn aggregates spread throughout the brain during disease progression, suggesting mechanisms of intercellular seeding. Formation of alpha-Syn amyloid fibrils is observed in vitro and fibrillar alpha-Syn has been purified from patient brains, but recent reports questioned whether disease-relevant alpha-Syn aggregates are fibrillar in structure. Here we use cryo-electron tomography (cryo-ET) to image neuronal Lewy body-like alpha-Syn inclusions in situ at molecular resolution. We show that the inclusions consist of alpha-Syn fibrils crisscrossing a variety of cellular organelles such as the endoplasmic reticulum (ER), mitochondria and autophagic structures, without interacting with membranes directly. Neuronal inclusions seeded by recombinant or MSA patient-derived alpha-Syn aggregates have overall similar architecture, although MSA-seeded fibrils show higher structural flexibility. Using gold-labeled seeds we find that aggregate nucleation is predominantly mediated by alpha-Syn oligomers, with fibrils growing unidirectionally from the seed. Our results conclusively demonstrate that neuronal alpha-Syn inclusions contain alpha-Syn fibrils intermixed with cellular membranes, and illuminate the mechanism of aggregate nucleation. ### Competing Interest Statement The authors have declared no competing interest.
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