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

Abstract α-Synuclein (α-Syn) oligomers play a critical role in the pathogenesis of Parkinson's disease (PD). α-Syn oligomers inducing neuronal death are thought to be associated with the mitochondrial dysfunction and oxidative stress. A chronic PD mouse model was created by daily intragastric administration of rotenone (5 mg/kg, 12 weeks). We analysed the progression of α-Syn aggregates from the gut to the midbrain together with oxidative stress levels and mitochondrial morphology in neurons of the substantia nigra in these mice. Our results showed that α-Syn oligomers were accumulated in the midbrain of the wild-type mice sequentially. The number of dopaminergic neurons was significantly reduced in the rotenone-treated mice. These mice also showed 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. Collectively, these findings suggest that α-Syn oligomers induce neuronal death at least in part via mitochondrial dysfunction and oxidative stress.