Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts

Timo Strohäker, Byung Chul Jung, Shu-Hao Liou, Claudio O. Fernandez, Dietmar Riedel, Stefan Becker, Glenda M. Halliday, Marina Bennati, Woojin S. Kim (), Seung-Jae Lee () and Markus Zweckstetter ()
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Timo Strohäker: German Center for Neurodegenerative Diseases (DZNE)
Byung Chul Jung: Seoul National University
Shu-Hao Liou: RG EPR Spectroscopy, Max Planck Institute for Biophysical Chemistry
Claudio O. Fernandez: Max Planck Laboratory for Structural Biology, Chemistry and Molecular Biophysics of Rosario (MPLbioR, UNR-MPIbpC)
Dietmar Riedel: Max Planck Institute for Biophysical Chemistry
Stefan Becker: Max Planck Institute for Biophysical Chemistry
Glenda M. Halliday: The University of Sydney
Marina Bennati: RG EPR Spectroscopy, Max Planck Institute for Biophysical Chemistry
Woojin S. Kim: The University of Sydney
Seung-Jae Lee: Seoul National University
Markus Zweckstetter: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13564-w

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