Prion Disease Therapeutics

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

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 drug 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. We and our collaborators tested 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. Brazilin preserves the natively unfolded state of -syn by stabilizing the compact conformation of the -syn monomer over the aggregation-competent open conformation. Molecular docking of Brazilin shows the molecule to interact both with unfolded -syn molecules and with the cross- 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.