Abstract
Parkinson's disease is the second most common neurodegenerative disease and its pathogenesis is closely associated with oxidative stress. Deposition of aggregated α‐synuclein (α‐Syn) occurs in familial and sporadic forms of Parkinson's disease. Here, we studied the effect of oligomeric α‐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 α‐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 α‐Syn on lipid peroxidation. Inhibition of lipid peroxidation with D‐PUFAs further protected cells from cell death induced by oligomeric α‐Syn. Thus, lipid peroxidation induced by misfolding of α‐Syn may play an important role in the cellular mechanism of neuronal cell loss in Parkinson's disease. We have found that aggregated α‐synuclein‐induced production of reactive oxygen species (ROS) that subsequently stimulates lipid peroxidation and cell death in neurons and astrocytes. Specific inhibition of lipid peroxidation by incubation with reinforced polyunsaturated fatty acids (D‐PUFAs) completely prevented the effect of α‐synuclein on lipid peroxidation and cell death.
Highlights
The ability of alpha-synuclein to produce reactive oxygen species (ROS) depends on the state of aggregation In agreement with our previous publication (Cremades et al 2012) we have found that in rat cortical primary co-cultures of neurons and astrocytes, application of 100 nM aggregated a-Syn but not non-aggregated (100 nM monomeric) a-Syn significantly increased the rate of ROS production (Fig. 1a), measured as the rate of increase in HEt ratio (494.6 Æ 17.6%, n = 9, p < 0.0001; and 126.3 Æ 19.5%, n = 9, p = 0.1962; of basal rate 100%, n = 9; Fig. 1b)
Lipid peroxidation is a part of the alpha-synuclein-induced damage to neurons Normally, production of ROS can be quenched by an effective antioxidant system which maintains redox balance
The effect of monomeric 100 nM a-Syn was indistinguishable from the basal rate (123.17 Æ 22.1% of basal rate; n = 132 cells; Fig. 2a and b). a-Syn penetrates the cells in 5–8 min (Cremades et al 2012) that suggests that this peptide can induce lipid peroxidation in all – plasmalemmal and intracellular membranes
Summary
We studied the effect of oligomeric a-Syn on one of the major markers of oxidative stress, lipid peroxidation, in primary co-cultures of neurons and astrocytes. Parkinson’s disease is a complex multifactorial disorder, one key causal factor remains the misfolding and aggregation of the protein a-Syn. The major histopathological hallmarks of Parkinson’s Disease (PD) include the loss of dopaminergic neurons in substantia nigra and the presence of Lewy bodies, which are intracellular inclusions of aggregated a-Syn. The exact mechanism by which aggregation of a-Syn induces neuronal cell death in the course of the disease is not yet clear; a growing body of evidence points towards a key role of oxidative stress in PD pathogenesis (Gandhi and Abramov 2012). We have previously shown (Cremades et al 2012) that exposure of neurons and astrocytes from a mixed primary culture to oligomeric forms of a-Syn leads to a dramatic increase in the basal ROS production
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