title: The sigma-1 receptor-zinc finger protein 179 pathway protects against hydrogen peroxide-induced cell injury.
abstract: The accumulation of reactive oxygen species (ROS) have implicated the pathogenesis of several human diseases including neurodegenerative disorders, stroke, and traumatic brain injury, hence protecting neurons against ROS is very important. In this study, we focused on sigma-1 receptor (Sig-1R), a chaperone at endoplasmic reticulum, and investigated its protective functions. Using hydrogen peroxide (H2O2)-induced ROS accumulation model, we verified that apoptosis-signaling pathways were elicited by H2O2 treatment. However, the Sig-1R agonists, dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS), reduced the activation of apoptotic pathways significantly. By performing protein-protein interaction assays and shRNA knockdown of Sig-1R, we identified the brain Zinc finger protein 179 (Znf179) as a downstream target of Sig-1R regulation. The neuroprotective effect of Znf179 overexpression was similar to that of DHEAS treatment, and likely mediated by affecting the levels of antioxidant enzymes. We also quantified the levels of peroxiredoxin 3 (Prx3) and superoxide dismutase 2 (SOD2) in the hippocampi of wild-type and Znf179 knockout mice, and found both enzymes to be reduced in the knockout versus the wild-type mice. In summary, these results reveal that Znf179 plays a novel role in neuroprotection, and Sig-1R agonists may be therapeutic candidates to prevent ROS-induced damage in neurodegenerative and neurotraumatic diseases.
authors.affiliation: Graduate Institute of Medical Science, Taipei Medical University, Taiwan.
authors.forename: Tzu-Chieh
authors.initials: TC
authors.lastname: Su
authors.affiliation: Graduate Institute of Medical Science, Taipei Medical University, Taiwan; Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Lin
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taiwan; Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, USA.
authors.forename: Pin-Tse
authors.initials: PT
authors.lastname: Lee
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Taiwan.
authors.forename: Shiu-Hwa
authors.initials: SH
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taiwan.
authors.forename: Tsung-Hsun
authors.initials: TH
authors.lastname: Hsieh
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taiwan.
authors.forename: Szu-Yi
authors.initials: SY
authors.lastname: Chou
authors.affiliation: Cellular Pathobiology Section, Intramural Research Program, National Institute on Drug Abuse, USA.
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
authors.affiliation: Institute of Bioinformatics and Biosignal Transduction, National Cheng Kung University, Taiwan.
authors.forename: Jan-Jong
authors.initials: JJ
authors.lastname: Hung
authors.affiliation: Graduate Institute of Medical Science, Taipei Medical University, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan.
authors.forename: Wen-Chang
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan. Electronic address: yclee@tmu.edu.tw.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Lee
authors.affiliation: Graduate Institute of Neural Regenerative Medicine, Taipei Medical University, Taiwan; Center for Neurotrauma and Neuroregeneration, Taipei Medical University, Taiwan. Electronic address: chuangcy@tmu.edu.tw.
authors.forename: Jian-Ying
authors.initials: JY
authors.lastname: Chuang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D003687:Dehydroepiandrosterone / Q000008:administration & dosage; D019314:Dehydroepiandrosterone Sulfate / Q000008:administration & dosage; D055785:Gene Knockdown Techniques; D006861:Hydrogen Peroxide; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism*; D017480:Receptors, sigma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D004268:DNA-Binding Proteins; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D006861:Hydrogen Peroxide; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C113383:ZNF179 protein, mouse
keywords: DHEA/DHEAS; Hydrogen peroxide; Reactive oxygen species; Sig-1R; Znf179