The toxicity of accumulated α-synuclein plays a key role in the neurodegeneration of Parkinson's disease (PD). This study has demonstrated that iron in varying concentrations (up to 400 µM) causes an increase in α-synuclein content in SH-SY5Y cells associated with mitochondrial depolarization, decreased cellular ATP content and loss of cell viability during incubation up to 96 h. Knocking-down α-synuclein expression prevents cytotoxic actions of iron, which can also be prevented by cyclosporine A (a blocker of mitochondrial permeability transition pore). These results indicate that iron cytotoxicity is mediated by α-synuclein acting on mitochondria. Likewise siRNA mediated knock-down of Parkin causes an accumulation of α-synuclein accompanied by mitochondrial dysfunction and cell death during 48 h incubation under basal conditions, but these changes are not further aggravated by co-incubation with iron (400 µM). We have also analyzed mitochondrial dysfunction and cell viability in SH-SY5Y cells under double knock-down (α-synuclein and Parkin concurrently) conditions during incubation for 48 h with or without iron. Our results tend to suggest that iron inactivates Parkin in SH-SY5Y cells and thereby inhibits the proteasomal degradation of α-synuclein, and the accumulated α-synuclein causes mitochondrial dysfunction and cell death. These results have implications in the pathogenesis of sporadic PD and also familial type with Parkin mutations.

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