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. Here,...
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| Format: | Article |
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Frontiers Media S.A.
2019-12-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnmol.2019.00306/full |
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| author | Samuel Peña-Díaz Samuel Peña-Díaz Jordi Pujols Jordi Pujols María Conde-Giménez Anita Čarija Anita Čarija Esther Dalfo Esther Dalfo Jesús García Susanna Navarro Susanna Navarro Francisca Pinheiro Francisca Pinheiro Jaime Santos Jaime Santos Xavier Salvatella Xavier Salvatella Javier Sancho Salvador Ventura Salvador Ventura Salvador Ventura |
| author_facet | Samuel Peña-Díaz Samuel Peña-Díaz Jordi Pujols Jordi Pujols María Conde-Giménez Anita Čarija Anita Čarija Esther Dalfo Esther Dalfo Jesús García Susanna Navarro Susanna Navarro Francisca Pinheiro Francisca Pinheiro Jaime Santos Jaime Santos Xavier Salvatella Xavier Salvatella Javier Sancho Salvador Ventura Salvador Ventura Salvador Ventura |
| author_sort | Samuel Peña-Díaz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T20:44:18Z |
| format | Article |
| id | doaj.art-271de745d09441ae8c687f01fdd96906 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-23T20:44:18Z |
| publishDate | 2019-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-271de745d09441ae8c687f01fdd969062022-12-21T17:31:49ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992019-12-011210.3389/fnmol.2019.00306497170ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded PolymerizationSamuel Peña-Díaz0Samuel Peña-Díaz1Jordi Pujols2Jordi Pujols3María Conde-Giménez4Anita Čarija5Anita Čarija6Esther Dalfo7Esther Dalfo8Jesús García9Susanna Navarro10Susanna Navarro11Francisca Pinheiro12Francisca Pinheiro13Jaime Santos14Jaime Santos15Xavier Salvatella16Xavier Salvatella17Javier Sancho18Salvador Ventura19Salvador Ventura20Salvador Ventura21Institut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainDepartment of Biochemistry and Molecular and Cell Biology, Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainFaculty of Medicine, M2, Universitat Autonoma de Barcelona, Barcelona, SpainFaculty of Medicine, University of Vic – Central University of Catalonia, Vic, SpainInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainInstitute for Research in Biomedicine, The Barcelona Institute of Science and Technology, Barcelona, SpainCatalan Institute for Research and Advance Studies, Barcelona, SpainDepartment of Biochemistry and Molecular and Cell Biology, Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Zaragoza, SpainInstitut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona, Barcelona, SpainDepartament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Barcelona, SpainCatalan Institute for Research and Advance Studies, Barcelona, Spainα-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.https://www.frontiersin.org/article/10.3389/fnmol.2019.00306/fullParkinson’s diseaseα-synucleinamyloidprotein aggregationaggregation inhibitorCaenorhabditis elegans |
| spellingShingle | Samuel Peña-Díaz Samuel Peña-Díaz Jordi Pujols Jordi Pujols María Conde-Giménez Anita Čarija Anita Čarija Esther Dalfo Esther Dalfo Jesús García Susanna Navarro Susanna Navarro Francisca Pinheiro Francisca Pinheiro Jaime Santos Jaime Santos Xavier Salvatella Xavier Salvatella Javier Sancho Salvador Ventura Salvador Ventura Salvador Ventura ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization Frontiers in Molecular Neuroscience Parkinson’s disease α-synuclein amyloid protein aggregation aggregation inhibitor Caenorhabditis elegans |
| title | ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization |
| title_full | ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization |
| title_fullStr | ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization |
| title_full_unstemmed | ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization |
| title_short | ZPD-2, a Small Compound That Inhibits α-Synuclein Amyloid Aggregation and Its Seeded Polymerization |
| title_sort | zpd 2 a small compound that inhibits α synuclein amyloid aggregation and its seeded polymerization |
| topic | Parkinson’s disease α-synuclein amyloid protein aggregation aggregation inhibitor Caenorhabditis elegans |
| url | https://www.frontiersin.org/article/10.3389/fnmol.2019.00306/full |
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