Journal Article

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

Sancho, Javier, Pinheiro, Francisca, Conde-Giménez, María, Dalfo, Esther, Santos, Jaime, Salvatella, Xavier, Pujols, Jordi, Navarro, Susanna, Čarija, Anita, Ventura, Salvador, Peña-Díaz, Samuel, García, Jesús

2019

Overview

α-Synuclein (α-Syn) forms toxic intracellular protein inclusions and transmissible amyloid structures in Parkinson's disease (PD). Preventing α-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 α-Syn aggregation. ZPD-2 inhibits the aggregation of α-Syn and the A30P and H50Q familial variants at substoichiometric compound:protein ratios. In addition, the molecule prevents the spreading of α-Syn seeds in protein misfolding cyclic amplification assays. ZPD-2 is active against different α-Syn strains and blocks their seeded polymerization. Treating with ZPD-2 two different PD models that express α-Syn either in muscle or in dopaminergic (DA) neurons substantially reduces the number of α-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.

• Publisher: Frontiers Research Foundation,Frontiers Media S.A
• Subject: aggregation inhibitor / Amyloid / Caenorhabditis elegans / Disease / Dopamine / Dopamine receptors / High-throughput screening / Movement disorders / Neurodegeneration / Neurodegenerative diseases / Neuroscience / Parkinson's disease / Polymerization / protein aggregation / Protein folding / Proteins / Seeds / Self-assembly / Synuclein / Transmission electron microscopy / α-synuclein