title: Dysregulation of iron protein expression in the G93A model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by selective loss of motor neurons which leads to progressive paralysis and death by respiratory failure. Although the cause of sporadic ALS is still unknown, oxidative stress is suggested to play a major role in the pathogenesis of this disease and of the rare familial form, which often exhibits mutations of the superoxide dismutase 1 (SOD1) gene. Since enhanced iron levels are discussed to participate in oxidative stress and neuronal death, we analyzed the expression levels of Fe-related mRNAs in a cell culture ALS model with the G93A mutation of SOD1. We observed an increased total iron content in G93A-SOD1 SH-SY5Y neuroblastoma cells compared to wild-type (WT)-SOD1 cells. mRNA expression for transferrin receptor 1 (TfR1) and divalent metal transporter 1 was increased in G93A-SOD1 cells, which was in accordance with higher iron uptake. Experiments with the iron chelator deferoxamine revealed a normal reaction of WT and mutant cells to cytoplasmic iron depletion, i.e. TfR1 upregulation, suggesting a basically conserved function of the iron-responsive element/iron regulatory protein (IRE/IRP) pathway, designed to adapt gene expression to iron levels. Expression levels of mitoferrin 1 and 2, frataxin, and iron-sulfur cluster scaffold protein were also significantly increased in G93A-SOD1 cells, suggesting higher mitochondrial iron import and utilization in biosynthetic pathways within the mitochondria. Moreover, expression of these transcripts was further enhanced, if G93A-SOD1 cells were differentiated by retinoic acid (RA). Since RA treatment increased cytoplasmic reactive oxygen species (ROS) levels in these cells, an IRE/IRP independent, ROS-mediated mechanism may account for dysregulation of iron-related genes.
authors.affiliation: Department of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hadzhieva
authors.forename: E
authors.initials: E
authors.lastname: Kirches
authors.forename: A
authors.initials: A
authors.lastname: Wilisch-Neumann
authors.forename: D
authors.initials: D
authors.lastname: Pachow
authors.forename: M
authors.initials: M
authors.lastname: Wallesch
authors.forename: P
authors.initials: P
authors.lastname: Schoenfeld
authors.forename: I
authors.initials: I
authors.lastname: Paege
authors.forename: S
authors.initials: S
authors.lastname: Vielhaber
authors.forename: S
authors.initials: S
authors.lastname: Petri
authors.forename: G
authors.initials: G
authors.lastname: Keilhoff
authors.forename: C
authors.initials: C
authors.lastname: Mawrin
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005452:Fluoresceins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007501:Iron / Q000378:metabolism; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D027682:Cation Transport Proteins; D005452:Fluoresceins; D033862:Iron-Binding Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin; C561492:Slc25a37 protein, human; C503640:TFR2 protein, human; C029569:diacetyldichlorofluorescein; D014212:Tretinoin; D007501:Iron; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase