%0 Journal Article
%A Frieg, Benedikt
%A Geraets, James A.
%A Strohäker, Timo
%A Dienemann, Christian
%A Mavroeidi, Panagiota
%A Jung, Byung Chul
%A Kim, Woojin S.
%A Lee, Seung-Jae
%A Xilouri, Maria
%A Zweckstetter, Markus
%A Schröder, Gunnar F.
%T Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein
%J Communications biology
%V 5
%N 1
%@ 2399-3642
%C London
%I Springer Nature
%M FZJ-2022-05455
%P 1040
%D 2022
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ 36180728
%U <Go to ISI:>//WOS:000862402500005
%R 10.1038/s42003-022-03948-y
%U https://juser.fz-juelich.de/record/912258