Inhibition of ?-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm.

ABSTRACT: Synucleinopathies are a group of disorders characterized by the accumulation of ?-Synuclein amyloid inclusions in the brain. Preventing ?-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q ?-Synuclein variants in vitro and interferes with ?-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed ?-Synuclein amyloid fibrils. Studies in a Caenorhabditis elegans model of Parkinson's Disease, prove that these in vitro properties are translated into a significant reduction in the accumulation of ?-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.

SUBMITTER: Pena-Diaz S 

PROVIDER: S-EPMC7597392 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature