Doxycycline modifies alpha-synuclein aggregation pathway yielding a lacking toxicity novel oligomeric species

MARIA FLORENCIA GONZALEZ LIZARRAGA; BENJAMÍN SOCIAS; CESAR LUIS AVILA; CLARISA TORRES - BOGEAU; LEANDRO BARBOSA; ANDRES BINOLFI; CLAUDIO FERNANDEZ; ROSANGELA ITRI; DULCE PAPY-GARCIA; RITA RAISMAN-VOZARI; ROSANA CHEHÍN

Mar del Plata

Congreso; XXX CONGRESO ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACION EN NEUROCIENCIAS; 2015

The dopaminergic neuronal loss, observed in Parkinson disease, has been linked to the pathological aggregation of α-synuclein (AS) and its transcellular traffic in the dopaminergic system. The neuroprotective properties of tetracyclines in Parkinson?s disease animal models have been reported (1). However, the interaction between any member of this antibiotic family with α-synuclein has not been reported yet. In the present work we explore the mechanism by which doxycycline is able to exert a protective effect against α-synuclein mediated toxicity. According to NMR studies, doxycycline cannot interact with monomeric α-synuclein but, by using fluorescence and infrared spectroscopy together with electronic microscopy, we demonstrate the ability the antibiotic to interact with certain oligomeric species of α-synuclein leading to the formation of novel species structurally and morphologically different from the toxic ones. Moreover, these species are not capable of altering the permeability of model membranes neither diminishing the viability of dopaminergic cells shedding light into the mechanism of the neuroprotection conferred by tetracycline in Parkinson´s disease models. In addition we demonstrate that doxycycline may also inhibit the seeding effect of α-synuclein oligomers on the native protein in vitro. This study represents a milestone in the assessment of the feasibility of using doxycycline as a therapeutic agent in the treatment of neurodegenerative disease.