Modification of α-synuclein by lipid peroxidation products derived from polyunsaturated fatty acids promotes toxic oligomerization: Its relevance to Parkinson disease

Abstract

Recently, toxic α-synuclein oligomor, which can mediate cell-To-cell propagation is suggested to cause sporadic Parkinson disease. α-Synuclein interacts with membrane lipids especially polyunsatu- rated fatty acids to stabilize its three-dementional structure. Per- oxidation of polyunsaturated fatty acids may reduce their affinity to α-synuclein and peroxidation byproducts might modify α- synuclein. 4-Hydroxy-2-nonenal derived from n-6 polyunsaturated fatty acids was reported to modify α-synuclein to produce a toxic oligomer. Moreover, the accumulation of 4-hydroxy-2-nonenal, which could induce oligomeriztion of α-synuclein, was found in Parkinsonian brains. Docosahexaenoic acid, an n-3 polyunsaturated fatty acids abundant in the neuronal membrane, was also found to enhance α-synuclein oligomerization; however, the precise details of the chemical reaction involved are unclear. Propanoylated lysine, a specific indicator of docosahexaenoic acid oxidation, was increased in neuronal differentiated human neuroblastoma SH-SY5Y cells overexpressing α-synuclein. α-Synuclein might be modified by the peroxidation products and then, is degraded by the auto- phagy-lysosome system. In addition, in the cells overexpressing α- synuclein, the mitochondrial electrone transfer chain was found to be inhibited. Accumulation of abnormal α-synuclein modified by lipid radicals derived from polyunsaturated fatty acids may be not only an indicator of brain oxidative stress but also causative of neurodegeneration such as Parkinson disease by impairing mito-chondrial function.