Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity

Abnormal aggregation of alpha-synuclein (alpha-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 alpha-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 alpha-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 alpha-syn and results in greater cell toxicity. Consistent with these results, knockdown of alpha-syn expression prevents reduction of Nrf2 and HO-1 by ferrous iron, eliminates alpha-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 alpha-syn/iron cytotoxicity, whereby ferrous iron induces alpha-syn aggregation and neurotoxicity by inhibiting Nrf2/HO-1. Inhibition of Nrf2/HO-1 leads to more alpha-syn aggregation and greater toxicity induced by iron, creating a vicious cycle of iron accumulation, alpha-syn aggregation and HO-1 disruption in PD. (C) 2013 Elsevier Ltd. All rights reserved.