Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-22108-0
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Funding
- Graduate School of Quantitative Biosciences Munich
- European Commission [ERC-2012-SyG_318987-ToPAG]
- Horst Kubler-Stiftung
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [EXC 2067/1-390729940, EXC 2145 -390857198]
- Michael J. Fox Foundation for Parkinson's Research (MJFF)
- Aligning Science Across Parkinson's (ASAP) initiative
- ASAP [ASAP-000282]
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The study used cryo-electron tomography to show that neuronal alpha-Syn inclusions consist of a mixture of fibrils and cellular organelles, without direct interaction between the fibrils and membranes.
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.
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