Journal Article

DZNE-2020-07974

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts.

Strohäker, T. (First author)DZNE* ; Jung, B. C. ; Liou, S.-H. ; Fernandez, C. O. ; Riedel, D. ; Becker, S. ; Halliday, G. M. ; Bennati, M. ; Kim, W. S. ; Lee, S.-J. ; Zweckstetter, M. (Last author)DZNE*

2019
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-13564-w

Abstract: Parkinson's disease (PD) and Multiple System Atrophy (MSA) are clinically distinctive diseases that feature a common neuropathological hallmark of aggregated α-synuclein. Little is known about how differences in α-synuclein aggregate structure affect disease phenotype. Here, we amplified α-synuclein aggregates from PD and MSA brain extracts and analyzed the conformational properties using fluorescent probes, NMR spectroscopy and electron paramagnetic resonance. We also generated and analyzed several in vitro α-synuclein polymorphs. We found that brain-derived α-synuclein fibrils were structurally different to all of the in vitro polymorphs analyzed. Importantly, there was a greater structural heterogeneity among α-synuclein fibrils from the PD brain compared to those from the MSA brain, possibly reflecting on the greater variability of disease phenotypes evident in PD. Our findings have significant ramifications for the use of non-brain-derived α-synuclein fibrils in PD and MSA studies, and raise important questions regarding the one disease-one strain hypothesis in the study of α-synucleinopathies.

Keyword(s): Aged (MeSH) ; Aged, 80 and over (MeSH) ; Brain: metabolism (MeSH) ; Female (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Models, Molecular (MeSH) ; Multiple System Atrophy: diagnosis (MeSH) ; Multiple System Atrophy: metabolism (MeSH) ; Parkinson Disease: diagnosis (MeSH) ; Parkinson Disease: metabolism (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Protein Conformation (MeSH) ; Synucleinopathies: diagnosis (MeSH) ; Synucleinopathies: metabolism (MeSH) ; Tissue Extracts: metabolism (MeSH) ; alpha-Synuclein: chemistry (MeSH) ; alpha-Synuclein: metabolism (MeSH)

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Contributing Institute(s):

1. Translational Structural Biology (AG Zweckstetter)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2019

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