α-Synuclein oligomers induce the loss of dopaminergic neurons via mitochondrial dysfunction and oxidative stress in an intragastric rotenone mouse model of Parkinson’s disease

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Abstract Background α-Synuclein (α-Syn) oligomers play a critical role in the pathogenesis of Parkinson's disease (PD). Neuronal death induced by α-Syn oligomers is thought to be associated with mitochondrial dysfunction and oxidative stress. This study investigated the effect of α-Synuclein oligomers on mitochondrial dysfunction and oxidative stress in an intragastric rotenone mouse model of Parkinson’s disease and the human dopaminergic neuroblastoma (SH-SY5Y) cells. Methods A chronic PD mouse model was established by daily intragastric administration of rotenone (5 mg/kg, 12 weeks). α-Syn aggregation in midbrain was detected by western blot and immunofluorescence. Oxidative stress levels and mitochondrial morphology in neurons of the substantia nigra in these mice were tested by levels of malondialdehyde (MDA), super oxide dismutase (SOD), and glutathione peroxidase (GSH-Px) and transmission electron microscopy (TEM). The above results were validated in vitro by lentiviral overexpression and RNAi silencing of α-Syn expression in SH-SY5Y cells. Results α-Syn oligomers were accumulated in the midbrain of wild-type mice and the number of dopaminergic neurons was significantly reduced in the rotenone-treated mice. These mice also exhibited increased reactive oxygen species levels and morphological alterations of mitochondria in the midbrain. These results were reproduced in the α-Syn-transfected SH-SY5Y cells. Conclusion α-Syn oligomers induce neuronal death via mitochondrial dysfunction and oxidative stress.

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