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Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium

View ORCID ProfileGeorge R. Nahass, Yuanzi Sun, Yong Xu, View ORCID ProfileMark Batchelor, Madeleine Reilly, Iryna Benilova, Niraja Kedia, View ORCID ProfileKevin Spehar, View ORCID ProfileFrank Sobott, View ORCID ProfileRichard B. Sessions, View ORCID ProfileByron Caughey, View ORCID ProfileSheena E. Radford, View ORCID ProfileParmjit Jat, View ORCID ProfileJohn Collinge, View ORCID ProfileJan Bieschke
doi: https://doi.org/10.1101/2020.09.29.318220
George R. Nahass
1Colorado College, Colorado Springs, CO, USA
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
3Washington University in St. Louis, St Louis, MO, USA
7Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA
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Yuanzi Sun
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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Yong Xu
4Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT UK
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Mark Batchelor
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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Madeleine Reilly
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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Iryna Benilova
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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Niraja Kedia
3Washington University in St. Louis, St Louis, MO, USA
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Kevin Spehar
3Washington University in St. Louis, St Louis, MO, USA
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Frank Sobott
4Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT UK
5Biomolecular and Analytical Mass Spectrometry group, University of Antwerp, Antwerp, Belgium
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Richard B. Sessions
6Biomedical Sciences Building, University Walk, Bristol, BS8 1TD, UK
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Byron Caughey
7Rocky Mountain Laboratories, NIAID, NIH, Hamilton, MT, USA
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Sheena E. Radford
4Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT UK
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Parmjit Jat
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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John Collinge
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
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Jan Bieschke
2University College London Institute of Prion Diseases / MRC Prion Unit, London, UK
3Washington University in St. Louis, St Louis, MO, USA
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  • For correspondence: j.bieschke@ucl.ac.uk
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ABSTRACT

Alpha-synuclein (α-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinson’s disease, form via nucleation dependent polymerization and can replicate by a seeding mechanism. Brazilin, a small molecule derived from red cedarwood trees in Brazil, has been shown to inhibit the fibrillogenesis of amyloid-beta (Aβ) and α-syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded α-syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of α-syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on Aβ. Brazilin preserves the natively unfolded state of α-syn by stabilizing the compact conformation of the α-syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded α-syn monomers and with the cross-β sheet structure of α-syn fibrils. Brazilin eliminates seeding competence of α-syn assemblies from Parkinson’s disease patient brain tissue, and treatment of pre-formed fibril assemblies with Brazilin significantly reduces their toxicity in primary neurons. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson’s Disease.

Highlights

  • - The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar α-syn

  • - Brazilin shifts the equilibrium away from aggregation-competent monomer conformations

  • - Brazilin inactivates seeding-competent α-syn isolated from Parkinson patients’ brains

  • - Brazilin detoxifies α-syn aggregation intermediates and stabilizes mature amyloid fibrils

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Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted October 01, 2020.
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Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
George R. Nahass, Yuanzi Sun, Yong Xu, Mark Batchelor, Madeleine Reilly, Iryna Benilova, Niraja Kedia, Kevin Spehar, Frank Sobott, Richard B. Sessions, Byron Caughey, Sheena E. Radford, Parmjit Jat, John Collinge, Jan Bieschke
bioRxiv 2020.09.29.318220; doi: https://doi.org/10.1101/2020.09.29.318220
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Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
George R. Nahass, Yuanzi Sun, Yong Xu, Mark Batchelor, Madeleine Reilly, Iryna Benilova, Niraja Kedia, Kevin Spehar, Frank Sobott, Richard B. Sessions, Byron Caughey, Sheena E. Radford, Parmjit Jat, John Collinge, Jan Bieschke
bioRxiv 2020.09.29.318220; doi: https://doi.org/10.1101/2020.09.29.318220

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