Home > Articles > Published articles > Inhibition of α-synuclein aggregation and mature fibril disassembling with a minimalistic compound, ZPDm |
Date: | 2020 |
Abstract: | Synucleinopathies are a group of disorders characterized by the accumulation of α-Synuclein amyloid inclusions in the brain. Preventing α-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 α-Synuclein variants in vitro and interferes with α-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed α-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 α-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. |
Grants: | Ministerio de Economía y Competitividad BIO2016-78310-R Ministerio de Economía y Competitividad BFU2016-78232-P Instituto de Salud Carlos III PH613883/ERDF/ESF Ministerio de Economía y Competitividad BIO2015-70092-R European Commission 648201 |
Note: | Altres ajuts: ICREA-Academia. The Fundación La Marató de TV3 (Ref. 20144330). The Gobierno de Aragón (E45_17R). |
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: | α-synuclein ; Protein aggregation ; Amyloid inhibitor ; Parkinson's disease ; Synucleinopathies ; Small molecules |
Published in: | Frontiers in Bioengineering and Biotechnology, Vol. 8 (October 2020) , art. 588947, ISSN 2296-4185 |
12 p, 2.4 MB |