Repurposing tetracyclines for treatment of Synucleinopathies

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

Buenos Aires

Congreso; 2nd FALAN Congress; 2016

Federation of Latin American and Caribbean Neuroscience Societies

Synucleinophaties are progressive neurodegenerative disorders characterized by the abnormal aggregation of the presynaptic protein α-synuclein. It is now accepted that cytotoxic α-synucleinaggregates 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 welltolerateddrug that cross the blood-brain-barrier and possess anti-inflammatory properties, has been proved effective in modulating the aggregation process of some disease-associatedproteins. 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 ofoligomeric 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, achemically modified tetracycline without antibiotic activity. Our results suggest that doxycycline and COL-3 could be repositioned for the treatment of synucleinopathies