TY  - JOUR
ID  - discovery10122470
N2  - Alpha-synuclein (?-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 (A?) and ?-syn as well as remodel mature fibrils and reduce cytotoxicity. 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 alters conformational equilibria in two separate points of the assembly mechanism: Brazilin preserves the natively unfolded state of ?-syn by specifically binding to the compact conformation of the ?-syn monomer. Brazilin also eliminates seeding competence of ?-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 ?-syn monomers and with the cross-? sheet structure of ?-syn fibrils. Our findings suggest that Brazilin has substantial potential as a neuroprotective and therapeutic agent for Parkinson?s Disease.
UR  - https://doi.org/10.1016/j.jmb.2021.166878
PB  - Elsevier BV
JF  - Journal of Molecular Biology
KW  - alpha-synuclein
KW  -  Brazilin
KW  -  Amyloid
KW  -  Parkinson?s Disease
KW  -  Polyphenol
KW  -  Natural Compound
KW  -  Neurodegeneration
KW  -  RT-QuIC
KW  -  Docking
KW  -  Neurotoxicity
A1  - Nahass, GR
A1  - Sun, Y
A1  - Xu, Y
A1  - Batchelor, M
A1  - Reilly, M
A1  - Benilova, I
A1  - Kedia, N
A1  - Spehar, K
A1  - Sobott, F
A1  - Sessions, RB
A1  - Caughey, BW
A1  - Radford, SE
A1  - Jat, P
A1  - Collinge, J
A1  - Bieschke, J
TI  - Brazilin Removes Toxic Alpha-Synuclein and Seeding Competent Assemblies from Parkinson Brain by Altering Conformational Equilibrium
VL  - 433
AV  - public
Y1  - 2021/04/16/
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
IS  - 8
ER  -