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 S Jat, John Collinge, Jan Bieschke

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 as well as remodel mature fibrils and reduce cytotoxicity. 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 alters conformational equilibria in two separate points of the assembly mechanism: Brazilin preserves the natively unfolded state of α-syn by specifically binding to the compact conformation of the α-syn monomer. Brazilin also eliminates seeding competence of α-syn assemblies from Parkinson's disease patient brain tissue, and reduces toxicity of pre-formed assemblies in primary neurons by inducing the formation of large fibril clusters. 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. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson's disease.

Original languageEnglish
Article number166878
Pages (from-to)166878
JournalJournal of Molecular Biology
Volume433
Issue number8
DOIs
Publication statusPublished - 16 Apr 2021

Bibliographical note

Funding Information:
Research was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health grant number 1R21NS101588-01A1 to JB. YX, FS and SER thank the Wellcome Trust for funding (204963). The native IM-MS was performed on a Synapt HDMS mass spectrometer purchased with funds from the BBSRC through its Research Equipment Initiative scheme (BB/E012558/1). This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (BC) and by the UK Medical Research Council (JC). The authors thank D. Sangar for help in protein preparation and EM, A. Wenborn for mass spectrometry of Brazilin and S. Singamaneni (Washington University in St Louis) for use of AFM. RBS thanks the University of Bristol ACRC for access to the ARM cluster Catalyst and the GW4 Consortium for access to the ARM cluster ISAMBARD. We would also like to gratefully acknowledge Dr. Ankit Srivastava (RML) for his assistance in EM grid and K23Q ?-syn preparation. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding Information:
Research was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health grant number 1R21NS101588-01A1 to JB. YX, FS and SER thank the Wellcome Trust for funding (204963). The native IM-MS was performed on a Synapt HDMS mass spectrometer purchased with funds from the BBSRC through its Research Equipment Initiative scheme (BB/E012558/1). This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (BC) and by the UK Medical Research Council (JC). The authors thank D. Sangar for help in protein preparation and EM, A. Wenborn for mass spectrometry of Brazilin and S. Singamaneni (Washington University in St Louis) for use of AFM. RBS thanks the University of Bristol ACRC for access to the ARM cluster Catalyst and the GW4 Consortium for access to the ARM cluster ISAMBARD. We would also like to gratefully acknowledge Dr. Ankit Srivastava (RML) for his assistance in EM grid and K23Q α-syn preparation.

Publisher Copyright:
© 2021

Keywords

  • Amyloid/metabolism
  • Amyloid beta-Peptides/metabolism
  • Animals
  • Benzopyrans/chemistry
  • Brain/metabolism
  • Humans
  • Mice
  • Molecular Conformation
  • Molecular Docking Simulation
  • Neurons
  • Parkinson Disease/metabolism
  • alpha-Synuclein/chemistry

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