title: Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b - implication in the pathogenesis of Parkinson's disease.
abstract: The pathogenesis of Parkinson's disease (PD) is not completely understood, Zinc (Zn(2+) ) and dopamine (DA) have been shown to involve in the degeneration of dopaminergic cells. By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn(2+) and DA-induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn(2+) treatment and raised to an even higher level by Zn(2+) plus DA treatment. Zn(2+) plus DA treatment-induced PC12 cell death was enhanced when there was over-expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross-talk with Gadd45b during Zn(2+) and DA treatment. The synergistic effects of Zn(2+) and DA on PC12 cell death can be accounted for by an activation of the Gadd45b-induced cell death pathway and an inhibition of p38/JNK survival pathway. Furthermore, the in vivo results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn(2+) /DA in the mouse brain and the level of Gadd45b mRNA is significantly higher in the substantia nigra of male PD patients than normal controls. The novel role of Gadd45b and its interactions with JNK and p38 will help our understanding of the pathogenesis of PD and help the development of future treatments for PD. Zinc and dopamine are implicated in the degeneration of dopaminergic neurons. We previously demonstrated that zinc and dopamine induced synergistic effects on PC12 cell death. Results from this study show that these synergistic effects can be accounted for by activation of the Gadd45b-induced cell death pathway and inhibition of the p38/JNK survival pathway. We provide in vitro and in vivo evidence to support a novel role for Gadd45b in the pathogenesis of Parkinson's disease.
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tien-Chun
authors.initials: TC
authors.lastname: Yang
authors.affiliation: Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Informatics, National Yang-Ming University, Taipei, Taiwan.
authors.forename: I-Fang
authors.initials: IF
authors.lastname: Chung
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jhih-Hang
authors.initials: JH
authors.lastname: Jiang
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ming-Ji
authors.initials: MJ
authors.lastname: Fann
authors.affiliation: Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan. lskao@ym.edu.tw.|Brain Research Center, National Yang-Ming University, Taipei, Taiwan. lskao@ym.edu.tw.
authors.forename: Lung-Sen
authors.initials: LS
authors.lastname: Kao
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000943:Antigens, Differentiation / Q000187:drug effects* / Q000235:genetics*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000633:toxicity*; D004357:Drug Synergism; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D016716:PC12 Cells; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D051381:Rats; D015032:Zinc / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D000111:Acetylcysteine; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D004298:Dopamine; D016166:Free Radical Scavengers; D048031:JNK Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D015032:Zinc; D048051:p38 Mitogen-Activated Protein Kinases; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C490125:Gadd45b protein, mouse
keywords: Gadd45b; JNK; Parkinson's disease; dopamine; p38; zinc