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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine Medicine > Munich Cluster for Systems Neurology (SyNergy) |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-102651-8 |
| Language: | English |
| Item ID: | 102651 |
| Date Deposited: | 05. Jun 2023, 15:40 |
| Last Modified: | 07. Jun 2024, 13:38 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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