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

Author

Listed:
  • Timo Strohäker

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Biophysical Chemistry)

  • 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)
    Universidad Nacional de Rosario)

  • Dietmar Riedel

    (Max Planck Institute for Biophysical Chemistry)

  • Stefan Becker

    (Max Planck Institute for Biophysical Chemistry)

  • Glenda M. Halliday

    (The University of Sydney
    University of New South Wales & Neuroscience Research Australia)

  • Marina Bennati

    (RG EPR Spectroscopy, Max Planck Institute for Biophysical Chemistry)

  • Woojin S. Kim

    (The University of Sydney
    University of New South Wales & Neuroscience Research Australia)

  • Seung-Jae Lee

    (Seoul National University)

  • Markus Zweckstetter

    (German Center for Neurodegenerative Diseases (DZNE)
    Max Planck Institute for Biophysical Chemistry
    University Medical Center Göttingen, University of Göttingen)

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.

Suggested Citation

  • 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 & Markus Zweckstetter, 2019. "Structural heterogeneity of α-synuclein fibrils amplified from patient brain extracts," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13564-w
    DOI: 10.1038/s41467-019-13564-w
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