Artículos de revistas
Repurposing doxycycline for synucleinopathies: Remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species
Fecha
2017-02Registro en:
González Lizarraga, Maria Florencia; Socias, Sergio Benjamin; Avila, Cesar Luis; Torres Bugeau, Clarisa Maria; Barbosa, Leandro R. S.; et al.; Repurposing doxycycline for synucleinopathies: Remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species; Nature Publishing Group; Scientific Reports; 7; 2-2017; 1-13
2045-2322
CONICET Digital
CONICET
Autor
González Lizarraga, Maria Florencia
Socias, Sergio Benjamin
Avila, Cesar Luis
Torres Bugeau, Clarisa Maria
Barbosa, Leandro R. S.
Binolfi, Andrés
Sepúlveda Díaz, Julia E.
Del Bel, Elaine
Fernandez, Claudio Oscar
Garcia Orozco Ep Papy, Dulce Maria
Itri, Rosangela
Raisman Vozari, Rita
Chehin, Rosana Nieves
Resumen
Synucleinophaties are progressive neurodegenerative disorders with no cure to date. An attractive strategy to tackle this problem is repurposing already tested safe drugs against novel targets. In this way, doxycycline prevents neurodegeneration in Parkinson models by modulating neuroinflammation. However, anti-inflammatory therapy per se is insufficient to account for neuroprotection. Herein we characterise novel targets of doxycycline describing the structural background supporting its effectiveness as a neuroprotector at subantibiotic doses. Our results show that doxycycline reshapes α-synuclein oligomers into off-pathway, high-molecular-weight species that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different β-sheet structural arrangement. These structural changes affect the α-synuclein ability to destabilize biological membranes, cell viability, and formation of additional toxic species. Altogether, these mechanisms could act synergically giving novel targets for repurposing this drug.