Akt/FoxO3A pathway: signaling target for alpha-synuclein overexpression and Maneb-mediated neurotoxicity

CONDE, MELISA A.; IGLESIAS GONZÁLEZ, PABLO A.; ALZA, NATALIA P.; BENZI JUNCOS, ORIANA; URANGA, ROMINA MARÍA; SALVADOR, GABRIELA A.

Paraná

Congreso; Reunión Anual SAIB; 2018

Sociedad Argentina de Investigación Bioquímica y Biología Molecular

Alpha-synuclein (a-syn) overexpression and manganese-based pesticides such as Maneb (Mb) have been both implicated as etiological factors ofParkinson?s disease. We have previously reported the neuroprotective role of Akt/FoxO3a in amyloid beta- and Fe-induced injury. In this work, westudied the role of the above-mentioned pathway in the effect of Mb and/or a-syn overexpression on IMR-32 human neuroblastoma cells. Forthis purpose, we exposed these neurons for different times (24-72 h) to increasing Mb concentrations (6-24 μM) and evaluated the redox status,Akt/FoxO3a subcellular localization and phosphorylation levels, and cell viability. The same parameters were evaluated in neurons stablyoverexpressing the wild type form of α-syn and exposed to either Mb or its vehicle. Mb exposure provoked a time- and concentration-dependent decrease in neuronal viability. This cytotoxic effect was mediated by the increase inreactive oxygen species (ROS), lipid peroxides and membrane cell permeability (LDH release). Intriguingly, Mb exposure in a-syn overexpressing neurons showed decreased ROS content and LDH release, with no changes in lipid peroxides. Mb was also found to induce changes in a-syn aggregation and phosphorylation, as measured with the intracellular probe Thioflavin S and by immunocytochemistry.On the other hand, Mb exposure and a-syn overexpression unconnectedly triggered the increase in Akt and FoxO3a nuclear localization. However, Mb exposure in a-syn overexpressing neurons enhanced FoxO3a nuclear localization without increasing cell death. We hypothesize that FoxO3a might be an a-syn target related with its unexpected protective role.