Inhibition of a-Synuclein Aggregation and Mature Fibril Disassembling With a Minimalistic Compound, ZPDm

Peña-Díaz, S. ; Pujols, J. ; Pinheiro, F. ; Santos, J. ; Pallarés, I. ; Navarro, S. ; Conde-Gimenez, M. ; García, J. ; Salvatella, X. ; Dalfó, E. ; Sancho, J. (Universidad de Zaragoza) ; Ventura, S.

Resumen: 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.

Idioma: Inglés

DOI: 10.3389/fbioe.2020.588947

Año: 2020

Publicado en: Frontiers in Bioengineering and Biotechnology 8 (2020), 588947 [12 pp]
ISSN: 2296-4185

Factor impacto JCR: 5.89 (2020)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 12 / 73 = 0.164 (2020) - Q1 - T1

Factor impacto SCIMAGO: 1.081 - Bioengineering (Q1) - Histology (Q1) - Biotechnology (Q1) - Biomedical Engineering (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)