Artículo
Repurposing doxycycline for synucleinopathies: Remodelling of α-synuclein oligomers towards non-toxic parallel beta-sheet structured species
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
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Fecha de publicación:
02/2017
Editorial:
Nature Publishing Group
Revista:
Scientific Reports
ISSN:
2045-2322
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
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.
Palabras clave:
Synuclein
,
Amyloid
,
Inhibition
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Articulos(CCT - ROSARIO)
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos de CTRO.CIENTIFICO TECNOL.CONICET - ROSARIO
Articulos(INSIBIO)
Articulos de INST.SUP.DE INVEST.BIOLOGICAS
Articulos de INST.SUP.DE INVEST.BIOLOGICAS
Citación
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
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