97191 20210902121917.0 doi 10.3389/fbioe.2020.588947 sideral 120957 ART-2020-120957 eng Peña-Díaz, S. Inhibition of a-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm 2020 Access copy available to the general public Unrestricted Synucleinopathies are a group of disorders characterized by the accumulation of a-Synuclein amyloid inclusions in the brain. Preventing a-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 a-Synuclein variants in vitro and interferes with a-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed a-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 a-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. info:eu-repo/grantAgreement/ES/DGA/E45-17R info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 5.89 2020 MULTIDISCIPLINARY SCIENCES 12 / 73 = 0.164 2020 Q1 T1 1.081 2020 Bioengineering 2020 Q1 Histology 2020 Q1 Biotechnology 2020 Q1 Biomedical Engineering 2020 Q1 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Pujols, J. Pinheiro, F. Santos, J. Pallarés, I. Navarro, S. Conde-Gimenez, M. (orcid)0000-0003-4358-9110 García, J. Salvatella, X. Dalfó, E. Sancho, J. Universidad de Zaragoza (orcid)0000-0002-2879-9200 Ventura, S. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 8 (2020), 588947 [12 pp] Front. Bioeng. Biotechnol. Frontiers in Bioengineering and Biotechnology 2296-4185 449838 http://zaguan.unizar.es/record/97191/files/texto_completo.pdf Versión publicada 487212 http://zaguan.unizar.es/record/97191/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:97191 articulos driver 2021-09-02-10:46:21 ARTICLE