title: NFE2L2 variations reduce antioxidant response in patients with Parkinson disease.
abstract: Oxidative stress has been recognized as a risk factor of Parkinson's disease (PD) development. We hypothesized that decreased function of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2)-antioxidant response element (ARE) pathway might predispose to Parkinsonism. A case-control study was performed between NFE2L2 Single Nucleotide Polymorphism (SNP) and PD in a cohort of 765 unrelated patients with diagnosis of PD and 489 matched normal individuals. We found that c.351T>A, D117E (P = 0.003, OR = 2.8) and c.351T>A, D117E (P = 0.012, OR = 1.9) were significantly associated with PD. The risk allele of both polymorphisms showed a high frequency in our PD sample (c.351A: 19.7% and c.423T: 7.8%). The association between both c.351T>A and c.423G>T and PD was further confirmed in an independent case-control cohort consisting of 210 individuals with PD and 148 normal controls. We further found that over expression of D117E and Q141H variants of NFE2L2 reduced target genes expression of Glutathione S-transferase Pi 1 (GSTP1), Glutathione S-transferase Mu 1 (GSTM1), and Heme oxygenase 1 (HO-1) genes. NFE2L2 D117E and Q141H impaired activation of ARE-driven transcriptional activity. Our findings indicate that NFE2L2 may play an important role in the pathogenesis of PD in Chinese populations.
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: YaXing
authors.initials: Y
authors.lastname: Gui
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: LiShan
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Lv
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: WenMing
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: JinJia
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neurology, Sir Run Run Shaw Hospital, Affiliated with School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
authors.forename: XingYue
authors.initials: X
authors.lastname: Hu
mesh_terms: D000818:Animals; D061745:Antioxidant Response Elements; D001483:Base Sequence; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics*; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human
keywords: Gerotarget; Parkinson disease; oxidative stress; polymorphism