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- Title
Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein.
- Authors
Frieg, Benedikt; Geraets, James A.; Strohäker, Timo; Dienemann, Christian; Mavroeidi, Panagiota; Jung, Byung Chul; Kim, Woojin S.; Lee, Seung-Jae; Xilouri, Maria; Zweckstetter, Markus; Schröder, Gunnar F.
- Abstract
Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive and unremitting neurological diseases that are neuropathologically characterized by α-synuclein inclusions. Increasing evidence supports the aggregation of α-synuclein in specific brain areas early in the disease course, followed by the spreading of α-synuclein pathology to multiple brain regions. However, little is known about how the structure of α-synuclein fibrils influence its ability to seed endogenous α-synuclein in recipient cells. Here, we aggregated α-synuclein by seeding with homogenates of PD- and MSA-confirmed brain tissue, determined the resulting α-synuclein fibril structures by cryo-electron microscopy, and characterized their seeding potential in mouse primary oligodendroglial cultures. The combined analysis shows that the two patient material-amplified α-synuclein fibrils share a similar protofilament fold but differ in their inter-protofilament interface and their ability to recruit endogenous α-synuclein. Our study indicates that the quaternary structure of α-synuclein fibrils modulates the seeding of α-synuclein pathology inside recipient cells. It thus provides an important advance in the quest to understand the connection between the structure of α-synuclein fibrils, cellular seeding/spreading, and ultimately the clinical manifestations of different synucleinopathies. Quaternary structure of α-synuclein fibrils characterized from human patients with Parkinson's disease and Multiple System Atrophy modulates seeding in mouse primary oligodendroglial cultures.
- Subjects
QUATERNARY structure; ALPHA-synuclein; MULTIPLE system atrophy; PARKINSON'S disease
- Publication
Communications Biology, 2022, Vol 5, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-022-03948-y