ZPD-2, a small compound that inhibits α-synuclein amyloid aggregation and its seeded polymerization
Peña Díaz, Samuel (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pujols Pujol, Jordi (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Conde Giménez, María (Universidad de Zaragoza. Instituto Universitario de Investigación de Biocomputación y Física de Sistemas Complejos)
Carija, Anita (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Dalfo, Esther (Universitat Autònoma de Barcelona. Facultat de Medicina)
García, Jesús (Institut de Recerca Biomèdica de Lleida)
Navarro, Susanna (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Pinheiro, Francisca (Universitat Autònoma de Barcelona. Institut de Biotecnologia i de Biomedicina "Vicent Villar Palasí")
Santos, Jaime (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Salvatella, Xavier (Institut de Recerca Biomèdica de Lleida)
Sancho, Javier (Universidad de Zaragoza. Instituto Universitario de Investigación de Biocomputación y Física de Sistemas Complejos)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2019
Abstract:	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.
Grants:	European Commission 648201 Ministerio de Economía y Competitividad BIO2015-70092-R Ministerio de Economía y Competitividad BIO2016-78310-R Ministerio de Economía y Competitividad BFU2016-78232-P
Note:	Altres ajuts: SV was supported by the ICREA (ICREA-Academia 2015) and the Fundación La Marató de TV3 (Ref. 20144330). JavS was supported by the Gobierno de Aragón (E45_17R). ED was supported by the Instituto de Salud Carlos III (PH613883/ERDF/ESF).
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Parkinson's disease ; α-synuclein ; Amyloid ; Protein aggregation ; Aggregation inhibitor ; Caenorhabditis elegans ; Neurodegeneration
Published in:	Frontiers in molecular neuroscience, Vol. 12 (Dec. 2019) , art. 306, ISSN 1662-5099

DOI: 10.3389/fnmol.2019.00306
PMID: 31920537

12 p, 3.6 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut de Biotecnologia i de Biomedicina (IBB)
Articles > Research articles
Articles > Published articles