Nrf2 pathway activation upon rotenone treatment in human iPSC-derived neural stem cells undergoing differentiation towards neurons and astrocytes. (September 2017)

• Record Type: Journal Article
• Authors: Pistollato, Francesca; Canovas-Jorda, David; Zagoura, Dimitra; Bal-Price, Anna
• Is Part Of: Neurochemistry international. Volume 108(2017)
• Page Start: 457
• Page End: 471
• Publication Date: 2017-09
• Subjects: Neural stem cells -- Rotenone -- Nrf2 pathway -- Astrocyte -- Dopaminergic neurons -- Neurite length -- Neurotoxicity; AOP Adverse Outcome Pathway -- ARE Antioxidant-Responsive-Element -- DA Dopaminergic -- DIV days in vitro -- GABA Gamma-Aminobutyric Acid -- GABRA1 Gamma-Aminobutyric Acid Type A Receptor Alpha1 Subunit -- GABRA3 Gamma-Aminobutyric Acid Type A Receptor Alpha3 Subunit -- GAP43 Growth Associated Protein 43 -- GAPDH Glyceraldehyde 3-phosphate dehydrogenase -- GFAP Glial FibrillaryAcidic Protein -- GSR Glutathione Reductase -- GRIA1 Glutamate Ionotropic Receptor AMPA Type Subunit 1 -- HCI High Content Imaging -- hESCs Human Embryonic Stem Cells -- hiPSCs Human Induced Pluripotent Stem Cells -- HMOX1 Heme Oxygenase-1 -- IATA Integrated Approaches to Testing and Assessment -- Keap1 Kelch-like ECH-Associated Protein 1 -- MAP2 Microtubule-Associated Protein 2 -- MAPT Microtubule-Associated Protein Tau -- MEA Multi Electrode Array -- MFR Mean Firing Rate -- MOA Mode of Action -- NF200 Neurofilament 200 -- NQO1 NAD(P)H Quinone Oxidoreductase 1 -- NR4A2 Nuclear Receptor Subfamily 4 Group A Member 2 -- Nrf2 Nuclear Factor (erythroid-derived 2)-like 2 -- NSCs Neural Stem Cells -- Pax6 Paired Box 6 -- PSCs Pluripotent Stem Cells -- SRXN1 Sulfiredoxin1 -- SYP Synaptophysin -- TH Tyrosine Hydroxylase -- VGlut1 Vesicular Glutamate Transporter 1; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2017.06.006
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Activation of Nrf2/ARE signaling pathway occurs ubiquitously in most cell types upon induction of oxidative stress. Rotenone, an inhibitor of mitochondrial complex I, can be used to trigger oxidative stress, stimulate the activation of Nrf2 pathway in neuronal and astrocytic cells and assess neurotoxicity. We have previously demonstrated that an acute treatment with rotenone can induce Nrf2 activation, which leads to astrocyte activation and dopaminergic (DA) neuronal cell death in a mixed neuronal/astrocytic cell model derived from human induced pluripotent stem cells (hiPSCs). In this study, we characterized the effects of a repeated dose treatment with rotenone (14 days) on hiPSC-derived neural stem cells (NSCs) undergoing differentiation, assessing the expression and the activation of the Nrf2 pathway. Our results show that Nrf2 signaling increases during NSC differentiation. Moreover, we observed that rotenone treatment induced a progressive activation of Nrf2 signaling together with a induction of astrocyte reactivity, a reduction of neurite length leading to neuronal cell death, in particular of DA neurons. Altogether these data indicate that hiPSC-NSC models are relevant test systems for the evaluation of Nrf2 pathway activation upon induced oxidative stress, allowing further understanding of the molecular mechanisms underlying exposure to (developmental) neurotoxicants. Highlights: hiPSC-derived NSCs respond to Nrf2 activation upon sub-chronic rotenone exposure. Rotenone-induced oxidative stress activates Nrf2/ARE signaling pathway. Nrf2 signaling increases during NSC differentiation into neurons/astrocytes. Rotenone causes astrocyte reactivity, neurite reduction and DA neuronal cell death.