Repurposing tetracyclines for treatment of Synucleinopathies

FLORENCIA GONZALEZ LIZARRAGA; BENJAMÍN SOCIAS; CESAR LUIS AVILA; CLARISA M. TORRES-BUGEAU; LEANDRO BARBOSA; ANDRES BINOLFI; CLAUDIO O. FERNANDEZ; DULCE PAPY-GARCIA; JULIA E. SEPÚLVEDA-DÍAZ; RITA RAISMAN-VOZARI; ROSANA CHEHÍN

Congreso; 2nd Federation of Latinoamerican and Caribbean Neuroscience Societies; 2016

Synucleinophaties are progressive neurodegenerative disorders characterized by the abnormal aggregation of the presynaptic protein α-synuclein. It is now accepted that cytotoxic α-synuclein aggregates are implicated in the neuronal demise observed in these pathologies. Currently, there are no effective therapeutic strategies that target α-synuclein aggregation and neurotoxicity. Recently, an important number of studies showed that tetracyclines have remarkable neuroprotective properties in Parkinson?s disease animal models. The antibiotic doxycycline, a well-tolerated drug that cross the blood-brain-barrier and possess anti-inflammatory properties, has been proved effective in modulating the aggregation process of some disease-associated proteins. Here we show for the first time that doxycycline is also capable to reshape α-synuclein oligomers into off-pathway high-molecular-weight aggregates that do not evolve into fibrils. Off-pathway species present less hydrophobic surface than on-pathway oligomers and display different beta-sheet structural arrangement. These structural changes abolish the ability of oligomeric α-synuclein to destabilize biological membranes, induce cytotoxicity and forme additional toxic species. We also show the effect on α-synuclein aggregation of COL-3, a chemically modified tetracycline without antibiotic activity. Our results suggest that doxycycline and COL-3 could be repositioned for the treatment of synucleinopathies.