Doxycycline leads to the formation of off-pathway non toxic alfa-Synuclein oligomers

GONZALEZ-LIZARRAGA, MF; CLARISA M. TORRES BUGEAU; SOCÍAS, B; AVILA CL; BARBOSA LR,; ITRI R,; PAPY-GARCIA D,; RAISMAN-VOZARI R,; AVILA CL, TORRES-BUGEAU CM, BARBOSA LR, MORANDÉ SALES E, OUIDJA MO, SOCÍAS SB, CELEJ MS, RAISMAN-VOZARI R, PAPY-GARCIA D, ITRI R, CHEHIN RN; CHEHÍN RN

Sierra de la Ventana

Congreso; XLIII Reunion Anual de la Sociedad Argentina de Biofisica; 2014

Sociedad Argentina de Biofisica

he dopaminergic neuronal loss observed in Parkinson disease has been linked to the pathological aggregation of alfa-synuclein (AS). Although this protein is mainly found in the cytosol, the presence of misfolded or aggregated AS in blood and cerebrospinal fluid suggests that it might play a role also at extracellular level. Indeed exposure to extracellular pre-aggreated AS-synuclein induces cytotoxicity in primary glia and human neuroblastoma cell cultures. Recently, an important number of studies showed that tetracyclines have remarkable neuroprotective properties in Parkinson disease animal models. In this work we explore the mechanism by which doxycycline, a semi-synthetic second-generation tetracycline, is able to exert such a protection against AS mediated toxicity. Through small angle x-ray diffraction and infrared spectroscopy we showed that doxycycline is able to affect the rate of alfa-synuclein oligomers formation. Moreover, using MTT viability assay, we observed that oligomers formed in the presence of doxycycline show decreased toxicity against dopaminergic cells. These oligomers seem to be off-pathway since they are not able to form fibrils detectable by means of ThT fluorescence assay or electronic microscopy. We propose that doxycycline is able to modify the aggregation pathway of AS leading to the formation of a nontoxic oligomer by binding to tyrosine residues as demonstrated by fluorescence quenching assays. This study represents a milestone in the assessment of the feasibility of using doxycycline as a therapeutic agent in the treatment of Parkinson disease.