ZPD-2, a small compound that inhibits α-synuclein amyloid aggregation and its seeded polymerization

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. H...

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Detalles Bibliográficos
Autores: Peña Díaz, Samuel|||0000-0002-2902-823X, Pujols Pujol, Jordi|||0000-0001-9424-5866, Conde Giménez, María|||0000-0003-4358-9110, Carija, Anita|||0000-0001-5972-7448, Dalfo, Esther|||0000-0003-4677-8515, García, Jesús, Navarro, Susanna|||0000-0001-8160-9536, Garcia de Carvalho Pinheiro, Francisca|||0000-0003-3778-1528, Santos Suárez, Jaime|||0000-0001-9045-7765, Salvatella, Xavier|||0000-0002-8371-4185, Sancho Sanz, Javier|||0000-0002-2879-9200, Ventura, Salvador|||0000-0002-9652-6351
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Universitat Autònoma de Barcelona
Repositorio:Dipòsit Digital de Documents de la UAB
Idioma:inglés
OAI Identifier:oai:ddd.uab.cat:223739
Acceso en línea:https://ddd.uab.cat/record/223739
https://dx.doi.org/urn:doi:10.3389/fnmol.2019.00306
Access Level:acceso abierto
Palabra clave:Parkinson's disease
α-synuclein
Amyloid
Protein aggregation
Aggregation inhibitor
Caenorhabditis elegans
Neurodegeneration
Descripción
Sumario: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 wild-type α-Syn and the A30P and H50Q familial variants in vitro 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 Caenorhabditis elegans 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.

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