Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
| Autor: | Iryna Benilova, Niraja Kedia, Sheena E. Radford, Frank Sobott, Yuanzi Sun, Richard B. Sessions, Mark Batchelor, Kevin Spehar, Byron Caughey, John Collinge, George R. Nahass, Jan Bieschke, Parmjit S. Jat, Yong Xu, Madeleine Reilly |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Amyloid
animal diseases Molecular Conformation Brazilin Fibril Neuroprotection Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Structural Biology Animals Humans Benzopyrans heterocyclic compounds Cytotoxicity Molecular Biology 030304 developmental biology Alpha-synuclein Neurons 0303 health sciences Amyloid beta-Peptides Brain Fibrillogenesis Parkinson Disease Small molecule nervous system diseases Molecular Docking Simulation chemistry nervous system Biophysics alpha-Synuclein 030217 neurology & neurosurgery |
| Zdroj: | J Mol Biol |
| ISSN: | 0022-2836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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