Lipid peroxidation is essential for α-synuclein-induced cell death

Parkinson's disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated alpha-synuclein (alpha-Syn) occurs in familial and sporadic forms of Parkinson's disease. Here, we studied the effect of oligomeric alpha-Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co-cultures of neurons and astrocytes. We found that oligomeric but not monomeric alpha-Syn significantly increases the rate of production of reactive oxygen species, subsequently inducing lipid peroxidation in both neurons and astrocytes. Pre-incubation of cells with isotope-reinforced polyunsaturated fatty acids (D-PUFAs) completely prevented the effect of oligomeric alpha-Syn on lipid peroxidation. Inhibition of lipid peroxidation with D-PUFAs further protected cells from cell death induced by oligomeric alpha-Syn. Thus, lipid peroxidation induced by misfolding of alpha-Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson's disease.