TY  - JOUR
AU  - Frieg, Benedikt
AU  - Geraets, James A
AU  - Strohäker, Timo
AU  - Dienemann, Christian
AU  - Mavroeidi, Panagiota
AU  - Jung, Byung Chul
AU  - Kim, Woojin S
AU  - Lee, Seung-Jae
AU  - Xilouri, Maria
AU  - Zweckstetter, Markus
AU  - Schröder, Gunnar F
TI  - Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein.
JO  - Communications biology
VL  - 5
IS  - 1
SN  - 2399-3642
CY  - London
PB  - Springer Nature
M1  - DZNE-2022-01554
SP  - 1040
PY  - 2022
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  - 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.
KW  - alpha-Synuclein: metabolism
KW  - Animals
KW  - Cryoelectron Microscopy
KW  - Mice
KW  - Multiple System Atrophy: pathology
KW  - Parkinson Disease
KW  - Synucleinopathies
KW  - alpha-Synuclein: chemistry
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:36180728
C2  - pmc:PMC9525671
DO  - DOI:10.1038/s42003-022-03948-y
UR  - https://pub.dzne.de/record/165261
ER  -