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bioRxiv · 10.1101/2020.09.29.318220

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

Nahass, G. R.·Sun, Y.·Xu, Y.·Batchelor, M.·Reilly, M.·Benilova, I.·Kedia, N.·Spehar, K.·Sobott, F.·Sessions, R. B.·Caughey, B.·Radford, S. E.·Jat, P.·Collinge, J.·Bieschke, J.
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Abstract

Alpha-synuclein (-syn) fibrils, a major constituent of the neurotoxic Lewy Bodies in Parkinsons 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 (A{beta}) and -syn, prompting our inquiry in its mechanism of action. Here we test the effects of Brazilin on both seeded and unseeded -syn fibril formation and show that the natural polyphenol inhibits fibrillogenesis of -syn by a unique mechanism that is distinct from other polyphenols and is also distinct from its effect on A{beta}. Brazilin preserves the natively unfolded state of -syn by stabilizing the compact conformation of the -syn monomer over the aggregation-competent extended conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded -syn monomers and with the cross-{beta} sheet structure of -syn fibrils. Brazilin eliminates seeding competence of -syn assemblies from Parkinsons 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 Parkinsons Disease. Highlights- The natural polyphenol Brazilin binds to monomeric, oligomeric and fibrillar -syn - Brazilin shifts the equilibrium away from aggregation-competent monomer conformations - Brazilin inactivates seeding-competent -syn isolated from Parkinson patients brains - Brazilin detoxifies -syn aggregation intermediates and stabilizes mature amyloid fibrils Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=117 HEIGHT=200 SRC="FIGDIR/small/318220v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@447629org.highwire.dtl.DTLVardef@a9871dorg.highwire.dtl.DTLVardef@1e5a83dorg.highwire.dtl.DTLVardef@8843eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Nahass, G. R., Sun, Y., Xu, Y., Batchelor, M., Reilly, M., Benilova, I., Kedia, N., Spehar, K., Sobott, F., Sessions, R. B., Caughey, B., Radford, S. E., Jat, P., Collinge, J., Bieschke, J.. 2020-10-01. Brazilin Removes Toxic alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium. https://doi.org/10.1101/2020.09.29.318220

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