New therapeutic perspective for Parkinsons disease: Doxycycline inhibits the formation of α-synuclein toxic species

FLORENCIA GONZÁLEZ LIZÁRRAGA; SERGIO B. SOCÍAS; CÉSAR L. ÁVILA; CLARISA M. TORRES-BUGEAU; LEANDRO R. S. BARBOSA; ANDRES BINOLFI; ROSANGELA ITRI; JULIA SEPULVEDA-DIAZ; DULCE PAPY- GARCIA ; ROSANA N. CHEHÍN; RITA RAISMAN-VOZARI

Congreso; 10 th FENS Forum of Neuroscience; 2016

Background: The aggregation of α-synuclein (α-syn) is considered the main pathogenic event in many neurological disorders known as synucleinopathies, such as Parkinson?s disease (PD). While the basis for toxicity has not been specifically elucidated, great efforts have been undertaken to setup compounds capable of inhibiting or reversing the α-syn aggregation. In animal models of PD, the neuroprotective properties of tetracyclines have been reported but knowledge of whether these effects are mediated by α-syn aggregation has not been reported yet.Aim: Explore the mechanism by which doxycycline, a semi-synthetic second-generation tetracycline, is able to exert a protective effect against α-syn aggregation mediated toxicity.Results: By using NMR, fluorescence and infrared spectroscopy together with electron microscopy we could demonstrate that doxycycline can bind to early oligomeric species of α-syn. This leads to the formation of new off-pathway species that have morphological and structural differences compared with on-pathway prefibrillar species. Doxycycline inhibits the recruitment of monomeric α-synuclein by off-pathway species, and the fibrilation process is blocked. In addition, off-pathway oligomers are not capable of altering the permeability of liposomes neither diminishing the viability of dopaminergic cell lines.Conclusion: Doxycycline is able to diminish α-syn mediated toxicity by redirecting aggregation into the formation of non-toxic off-pathway oligomers. This study represents a milestone in the assessment of the feasibility of using doxycycline as a therapeutic agent in the treatment of PD.