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Journal Article

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

MPS-Authors
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Strohäker,  T.
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

/persons/resource/persons209121

Liou,  S. H.
Research Group of Electron Paramagnetic Resonance, MPI for Biophysical Chemistry, Max Planck Society;

/persons/resource/persons15710

Riedel,  D.
Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons14824

Becker,  S.
Department of NMR Based Structural Biology, MPI for biophysical chemistry, Max Planck Society;

/persons/resource/persons14834

Bennati,  M.
Research Group of Electron Paramagnetic Resonance, MPI for Biophysical Chemistry, Max Planck Society;

/persons/resource/persons16093

Zweckstetter,  M.
Research Group of Protein Structure Determination using NMR, MPI for Biophysical Chemistry, Max Planck Society;

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Fulltext (public)

3181405.pdf
(Publisher version), 3MB

Supplementary Material (public)

3181405_Suppl_1.pdf
(Supplementary material), 940KB

3181405_Suppl_2.pdf
(Supplementary material), 956KB

3181405_Suppl_3.pdf
(Supplementary material), 2MB

Citation

Strohäker, T., Jung, B. C., Liou, S. H., Fernandez, C. O., Riedel, D., Becker, S., et al. (2019). Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts. Nature Communications, 10: 5535. doi:10.1038/s41467-019-13564-w.


Cite as: http://hdl.handle.net/21.11116/0000-0005-5568-7
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.