Abnormal aggregation of α-synuclein (α-syn) plays a critical role in the pathogenesis of Parkinson's disease (PD). Iron is also believed to serve as a major contributor by inducing oxidative stress and α-syn aggregation. Here, we report that down-regulation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) may contribute to iron-induced α-syn aggregation. In this study, we show that ferrous iron down-regulates Nrf2 and HO-1 in a time-dependent manner in SK-N-SH neuroblastoma cells. Levels of both Nrf2 and HO-1 are decreased even more by ferrous iron in SK-N-SH cells that overexpress α-syn and results in greater cell toxicity. Consistent with these results, knockdown of α-syn expression prevents reduction of Nrf2 and HO-1 by ferrous iron, eliminates α-syn aggregates, and protects SK-N-SH cells against ferrous iron-induced cell damage. Furthermore, increased HO-1 expression exerts a protective role against ferrous iron. These results support a new hypothesis of synergistic α-syn/iron cytotoxicity, whereby ferrous iron induces α-syn aggregation and neurotoxicity by inhibiting Nrf2/HO-1. Inhibition of Nrf2/HO-1 leads to more α-syn aggregation and greater toxicity induced by iron, creating a vicious cycle of iron accumulation, α-syn aggregation and HO-1 disruption in PD.
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