α-Synuclein (α-syn) represents the main component of the amyloid aggregates present in Parkinson's disease and other neurodegenerative disorders, collectively named synucleinopathies. Although α-syn is considered a natively unfolded protein, it shows great structural flexibility which allows the protein to adopt highly rich beta-sheet structures like protofibrils, oligomers and fibrils. In addition, this protein can adopt alpha-helix rich structures when interacts with fatty acids or acidic phospholipid vesicle membranes. When analyzing the toxicity of α-syn, protein oligomers are thought to be the main neurotoxic species by mechanisms that involve modification of intracellular calcium levels, mitochondrial and lysosomal function. Extracellular fibrillar α-syn promotes intracellular protein aggregation and shows many toxic effects as well. Nitro-fatty acids (nitroalkenes) represent novel pleiotropic anti-inflammatory signaling mediators that could interact with α-syn to exert unraveling actions. Herein, we demonstrated that nitro-oleic acid (NO2-OA) nitroalkylate α-syn, forming a covalent adduct at histidine-50. The nitroalkylated-α-syn exhibited strong affinity for phospholipid vesicles, moving the protein to the membrane compartment independent of composition of the membrane phospholipids. Moreover, NO2-OA-modified α-syn showed a reduced capacity to induce α-syn fibrillization compared to the non-nitrated oleic acid. From this data we hypothesize that nitroalkenes, in particular NO2-OA, may inhibit α-syn fibril formation exerting protective actions in Parkinson's disease.
Keywords: Michael adducts; Nitro-oleic acid; Nitroalkylation; Nitrofatty acid; Parkinson’s disease; α-Synuclein.