Targeting the intrinsically disordered structural ensemble of alpha-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease.

GERGELY TOTH; SHYRA J. GARDAI; WAGNER ZAGO; CARLOS W. BERTONCINI; NUNILO CREMADES; SUSAN L. ROY; MITALI A. TAMBE; JEAN-CHRISTOPHE ROCHE; CELINE GALVAGNION; GAIA SKIBINSKI; MICHELE VENDRUSCOLO; JOHN CHRISTODOULOU; CHRISTOPHER M. DOBSON; DALE SCHENK; LISA MC. CONLOGUE

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2014 vol. 9 p. 1 - 11

1932-6203

The misfolding of intrinsically disordered proteins such as alpha-synuclein, tau and the Abeta peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinson´s and Alzheimer´s diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets alpha-synuclein, a key protein in Parkinson´s disease. We found that this compound has substantial biological activity in cellular models of alpha-synuclein-mediated dysfunction, including rescue of α-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of alpha-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting alpha-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinson´s disease and related conditions.