Journal Article

DZNE-2022-01554

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. ; Geraets, J. A. ; Strohäker, T.DZNE* ; Dienemann, C. ; Mavroeidi, P. ; Jung, B. C. ; Kim, W. S. ; Lee, S.-J. ; Xilouri, M. ; Zweckstetter, M.DZNE* ; Schröder, G. F.

2022
Springer Nature London

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Please use a persistent id in citations: 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.

Keyword(s): alpha-Synuclein: metabolism (MeSH) ; Animals (MeSH) ; Cryoelectron Microscopy (MeSH) ; Mice (MeSH) ; Multiple System Atrophy: pathology (MeSH) ; Parkinson Disease (MeSH) ; Synucleinopathies (MeSH) ; alpha-Synuclein: chemistry (MeSH) ; alpha-Synuclein

Note: CC BY: https://creativecommons.org/licenses/by/4.0/

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Contributing Institute(s):

1. Structural Biology in Dementia (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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