ZPD-2, a Small Compound That Inhibits ?-Synuclein Amyloid Aggregation and Its Seeded Polymerization.

ABSTRACT: ?-Synuclein (?-Syn) forms toxic intracellular protein inclusions and transmissible amyloid structures in Parkinson's disease (PD). Preventing ?-Syn self-assembly has become one of the most promising approaches in the search for disease-modifying treatments for this neurodegenerative disorder. Here, we describe the capacity of a small molecule (ZPD-2), identified after a high-throughput screening, to inhibit ?-Syn aggregation. ZPD-2 inhibits the aggregation of wild-type ?-Syn and the A30P and H50Q familial variants in vitro at substoichiometric compound:protein ratios. In addition, the molecule prevents the spreading of ?-Syn seeds in protein misfolding cyclic amplification assays. ZPD-2 is active against different ?-Syn strains and blocks their seeded polymerization. Treating with ZPD-2 two different PD Caenorhabditis elegans models that express ?-Syn either in muscle or in dopaminergic (DA) neurons substantially reduces the number of ?-Syn inclusions and decreases synuclein-induced DA neurons degeneration. Overall, ZPD-2 is a hit compound worth to be explored in order to develop lead molecules for therapeutic intervention in PD.

SUBMITTER: Pena-Diaz S 

PROVIDER: S-EPMC6928008 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature