title: Role of α-synuclein aggregation and the nuclear factor E2-related factor 2/heme oxygenase-1 pathway in iron-induced neurotoxicity.
abstract: 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.
authors: Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao 266071, China.
authors: Qing
authors: Q
authors: He
authors: Ning
authors: N
authors: Song
authors: Fengjv
authors: F
authors: Jia
authors: Huamin
authors: H
authors: Xu
authors: Xiaojun
authors: X
authors: Yu
authors: Junxia
authors: J
authors: Xie
authors: Hong
authors: H
authors: Jiang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D055785:Gene Knockdown Techniques; D051547:Heme Oxygenase-1 / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007501:Iron; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495637:Nfe2l2 protein, rat; C497604:SNCA protein, human; C497606:Snca protein, rat; D051844:alpha-Synuclein; D007501:Iron; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1