doi:10.3389/fbioe.2020.588947engPeña-Díaz, S.Pujols, J.Pinheiro, F.Santos, J.Pallarés, I.Navarro, S.Conde-Gimenez, M.García, J.Salvatella, X.Dalfó, E.Sancho, J.Ventura, S.Inhibition of a-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDmART-2020-120957Synucleinopathies 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.2020http://zaguan.unizar.es/record/9719110.3389/fbioe.2020.588947http://zaguan.unizar.es/record/97191oai:zaguan.unizar.es:97191info:eu-repo/grantAgreement/ES/DGA/E45-17Rinfo:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-PFrontiers in Bioengineering and Biotechnology 8 (2020), 588947 [12 pp]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess