title: Neurotoxin-induced pathway perturbation in human neuroblastoma SH-EP cells.
abstract: The exact causes of cell death in Parkinson's disease (PD) remain unknown despite extensive studies on PD.The identification of signaling and metabolic pathways involved in PD might provide insight into the molecular mechanisms underlying PD. The neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)) induces cellular changes characteristic of PD, and MPP(+)-based models have been extensively used for PD studies. In this study, pathways that were significantly perturbed in MPP(+)-treated human neuroblastoma SH-EP cells were identified from genome-wide gene expression data for five time points (1.5, 3, 9, 12, and 24 h) after treatment. The mitogen-activated protein kinase (MAPK) signaling pathway and endoplasmic reticulum (ER) protein processing pathway showed significant perturbation at all time points. Perturbation of each of these pathways resulted in the common outcome of upregulation of DNA-damage-inducible transcript 3 (DDIT3). Genes involved in ER protein processing pathway included ubiquitin ligase complex genes and ER-associated degradation (ERAD)-related genes. Additionally, overexpression of DDIT3 might induce oxidative stress via glutathione depletion as a result of overexpression of CHAC1. This study suggests that upregulation of DDIT3 caused by perturbation of the MAPK signaling pathway and ER protein processing pathway might play a key role in MPP(+)-induced neuronal cell death. Moreover, the toxicity signal of MPP(+) resulting from mitochondrial dysfunction through inhibition of complex I of the electron transport chain might feed back to the mitochondria via ER stress. This positive feedback could contribute to amplification of the death signal induced by MPP(+).
authors.affiliation: Department of Biomolecular and Chemical Engineering, DongYang University, Yeongju 750-711, Korea.
authors.forename: Jin Hwan
authors.initials: JH
authors.lastname: Do
mesh_terms: D015655:1-Methyl-4-phenylpyridinium / Q000633:toxicity*; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000473:pathology; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015203:Reproducibility of Results; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: C497249:DDIT3 protein, human; D009498:Neurotoxins; D051742:Transcription Factor CHOP; D015655:1-Methyl-4-phenylpyridinium
keywords: 1-methyl-4-phenylpyridinium; Parkinson’s disease; SH-EP cells; gene regulation; pathway perturbation