title: Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion that encodes a polyglutamine tract in huntingtin (htt) protein. Dysregulation of brain iron homeostasis, oxidative stress and neurodegeneration are consistent features of the HD phenotype. Therefore, environmental factors that exacerbate oxidative stress and iron dysregulation may potentiate HD. Iron supplementation in the human population is common during infant and adult-life stages. In this study, iron supplementation in neonatal HD mice resulted in deterioration of spontaneous motor running activity, elevated levels of brain lactate and oxidized glutathione consistent with increased energetic dysfunction and oxidative stress, and increased striatal and motor cortical neuronal atrophy, collectively demonstrating potentiation of the disease phenotype. Oxidative stress, energetic, and anatomic markers of degeneration were not affected in wild-type littermate iron-supplemented mice. Further, there was no effect of elevated iron intake on disease outcomes in adult HD mice. We have demonstrated an interaction between the mutant huntingtin gene and iron supplementation in neonatal HD mice. Findings indicate that elevated neonatal iron intake potentiates mouse HD and promotes oxidative stress and energetic dysfunction in brain. Neonatal-infant dietary iron intake level may be an environmental modifier of human HD.
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: kberggre@uwyo.edu.
authors.forename: Kiersten L
authors.initials: KL
authors.lastname: Berggren
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA; Neuroscience Graduate Program, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: chenjianfang11@gmail.com.
authors.forename: Jianfang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: jfox8@uwyo.edu.
authors.forename: Julia
authors.initials: J
authors.lastname: Fox
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: jmill129@uwyo.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Miller
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: ldodds917@gmail.com.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Dodds
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: dugas@uw.edu.
authors.forename: Bryan
authors.initials: B
authors.lastname: Dugas
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: lvargas1@uwyo.edu.
authors.forename: Liset
authors.initials: L
authors.lastname: Vargas
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Amber
authors.initials: A
authors.lastname: Lothian
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Erin
authors.initials: E
authors.lastname: McAllum
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: irene.volitakis@florey.edu.au.
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: blaine.roberts@florey.edu.au.
authors.forename: Blaine
authors.initials: B
authors.lastname: Roberts
authors.affiliation: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: ashleyib@unimelb.edu.au.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA; Neuroscience Graduate Program, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: jfox7@uwyo.edu.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Fox
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements / Q000009:adverse effects*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D019803:Glutathione Disulfide / Q000819:agonists / Q000378:metabolism; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D058085:Iron Compounds / Q000009:adverse effects*; D051379:Mice; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D045442:Rotarod Performance Test; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D058085:Iron Compounds; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C515100:iron pentacarbonyl; D019803:Glutathione Disulfide
keywords: Gene environment interaction; Huntington’s; Iron; Neurodegeneration; Oxidative stress; Stereology