Journal Article

FZJ-2022-05455

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Quaternary structure of patient-homogenate amplified α-synuclein fibrils modulates seeding of endogenous α-synuclein

Frieg, B.FZJ* ; Geraets, J. A.FZJ* ; Strohäker, T. ; Dienemann, C. ; Mavroeidi, P. ; Jung, B. C. ; Kim, W. S. ; Lee, S.-J. ; Xilouri, M. ; Zweckstetter, M. (Corresponding author) ; Schröder, G. F. (Corresponding author)FZJ*

2022
Springer Nature London

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Please use a persistent id in citations: http://hdl.handle.net/2128/32950  doi:10.1038/s42003-022-03948-y

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.

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Contributing Institute(s):

1. Strukturbiochemie (IBI-7)

Research Program(s):

1. 5244 - Information Processing in Neuronal Networks (POF4-524) (POF4-524)

Appears in the scientific report 2022

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