DOXYCYCLINE CAN EFFICIENTLY SWITCH ALPHA-SYNUCLEIN EARLY AGGREGATION OLIGOMERS INTO NON-TOXIC SPECIES: REPURPOSING AN OLD DRUG AS NEUROPROTECTOR

GONZALES LIZARRAGA, MF; SOCIAS, S.B.; AVILA C.; BARBOSA L.; BINOLFI A.; SEPULVEDA DIAZ, J.; DEL-BEL, E.; FERNADEZ C.; PAPY GARCÍA; ITRI R.; CHEHÍN R.; RAISMAN VOZARI R.

Viena

Congreso; 13th Conferece on Alzheimer´s and Parkinson´s Diseases; 2017

Objectives: synucleinophaties are progressive disorders with no cure to date. An attractive strategy to tackle this problem is discovering new uses for approved drugs to provide the quickest possible transition from bench to bedside.Methods: we used a combination biophysical techniques like fluorescence and infrared spectroscopy, electronic microscopy, small angle X Ray scattering and NMR together with cellular biology approaches to assess the impact ofdoxycycline on α-synuclein aggregation.Results: we demonstrate the ability of doxycycline to interfere with the pathologic cycle involved in synucleinopathies at the aggregation level. We proved that doxycycline interacts with alpha-synuclein early aggregationintermediates leading to the formation of off-pathway species, with parallel beta-sheet content, that do not evolve into fibril formation. These aggregates are neither cytotoxic to dopaminergic cell lines, nor capable of disrupting theintegrity of liposomes membrane. Furthermore, doxycycline is also able to block the seeding capacity of alpha-synuclein preformed aggregates.