RT Journal Article
SR Electronic
T1 Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.29.318220
DO 10.1101/2020.09.29.318220
A1 Nahass, George R.
A1 Sun, Yuanzi
A1 Xu, Yong
A1 Batchelor, Mark
A1 Reilly, Madeleine
A1 Benilova, Iryna
A1 Kedia, Niraja
A1 Spehar, Kevin
A1 Sobott, Frank
A1 Sessions, Richard B.
A1 Caughey, Byron
A1 Radford, Sheena E.
A1 Jat, Parmjit
A1 Collinge, John
A1 Bieschke, Jan
YR 2020
UL http://biorxiv.org/content/early/2020/10/01/2020.09.29.318220.abstract
AB 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 fibrilsCompeting Interest StatementThe authors have declared no competing interest.