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By microarray analysis, we identified Gadd45b as a candidate molecule that mediates Zn<jats:sup>2+<\/jats:sup>and DA\u2010induced cell death; the mRNA and protein levels of Gadd45b are increased by Zn<jats:sup>2+<\/jats:sup>treatment and raised to an even higher level by Zn<jats:sup>2+<\/jats:sup>plus DA treatment. Zn<jats:sup>2+<\/jats:sup>plus DA treatment\u2010induced PC12 cell death was enhanced when there was over\u2010expression of Gadd45b and was decreased by knock down of Gadd45b. MAPK p38 and JNK signaling was able to cross\u2010talk with Gadd45b during Zn<jats:sup>2+<\/jats:sup>and DA treatment. The synergistic effects of Zn<jats:sup>2+<\/jats:sup>and DA on PC12 cell death can be accounted for by an activation of the Gadd45b\u2010induced cell death pathway and an inhibition of p38\/JNK survival pathway. Furthermore, the<jats:italic>in\u00a0vivo<\/jats:italic>results show that the levels of Gadd45b protein expression and phosphorylation of p38 were increased in the substantia nigra by the infusion of Zn<jats:sup>2+<\/jats:sup>\/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.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p><jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc13728-fig-0010-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>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\u2010induced cell death pathway and inhibition of the p38\/JNK survival pathway. We provide<jats:italic>in\u00a0vitro<\/jats:italic>and<jats:italic>in\u00a0vivo<\/jats:italic>evidence to support a novel role for Gadd45b in the pathogenesis of Parkinson's disease.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.13728","type":"journal-article","created":{"date-parts":[[2016,7,6]],"date-time":"2016-07-06T16:25:51Z","timestamp":1467822351000},"page":"120-133","source":"Crossref","is-referenced-by-count":24,"title":["Cell death caused by the synergistic effects of zinc and dopamine is mediated by a stress sensor gene Gadd45b \u2013 implication in the pathogenesis of Parkinson's disease"],"prefix":"10.1111","volume":"139","author":[{"given":"Tien\u2010Chun","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei\u2010Chun","family":"Wu","sequence":"additional","affiliation":[{"name":"Brain Research Center National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u2010Fang","family":"Chung","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Informatics National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhih\u2010Hang","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming\u2010Ji","family":"Fann","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lung\u2010Sen","family":"Kao","sequence":"additional","affiliation":[{"name":"Department of Life Sciences and Institute of Genome Sciences National Yang\u2010Ming University Taipei Taiwan"},{"name":"Brain Research Center National Yang\u2010Ming University Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,8,4]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"165","article-title":"Sequence and expression of a cDNA encoding MyD118: a novel myeloid differentiation primary response gene induced by multiple cytokines","volume":"6","author":"Abdollahi A.","year":"1991","journal-title":"Oncogene"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/308734a0"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2015.00091"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0301-0082(01)00003-X"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1602\/neurorx.2.3.484"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-8993(96)01056-6"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001837200"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4547(19990701)57:1<86::AID-JNR9>3.0.CO;2-E"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1039\/b926662c"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/35104560"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1989.tb07264.x"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/114.4.1953"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10522-006-9045-7"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1159\/000109536"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrn1671"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00775-011-0797-4"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2004-5-10-r80"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yfrne.2014.02.002"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M600950200"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M511560200"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(01)00148-6"},{"key":"e_1_2_7_23_1","first-page":"103","article-title":"Loss of dopaminergic neurons in parkinsonism: possible role of reactive dopamine metabolites","volume":"49","author":"Hastings T. 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