visitant ::
identificació
|
|||||||||||||||
Cerca | Lliura | Ajuda | Servei de Biblioteques | Sobre el DDD | Català English Español |
Pàgina inicial > Articles > Articles publicats > ZPD-2, a small compound that inhibits α-synuclein amyloid aggregation and its seeded polymerization |
Data: | 2019 |
Resum: | 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. |
Ajuts: | 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 |
Nota: | 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). |
Drets: | 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. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | Parkinson's disease ; α-synuclein ; Amyloid ; Protein aggregation ; Aggregation inhibitor ; Caenorhabditis elegans ; Neurodegeneration |
Publicat a: | Frontiers in molecular neuroscience, Vol. 12 (Dec. 2019) , art. 306, ISSN 1662-5099 |
12 p, 3.6 MB |