Neonatal iron supplementation potentiates oxidative stress, energetic dysfunction and neurodegeneration in the R6/2 mouse model of Huntington's disease

• Published in: Redox biology 2015-04, Vol.4 (C), p.363-374
• Main Authors: Berggren, Kiersten L, Chen, Jianfang, Fox, Julia, Miller, Jonathan, Dodds, Lindsay, Dugas, Bryan, Vargas, Liset, Lothian, Amber, McAllum, Erin, Volitakis, Irene, Roberts, Blaine, Bush, Ashley I, Fox, Jonathan H
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Behavior, Animal - drug effects; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - pathology; Dietary Supplements - adverse effects; Disease Models, Animal; Energy Metabolism - drug effects; Female; Gene environment interaction; Gene Expression; Glutathione Disulfide - agonists; Glutathione Disulfide - metabolism; Humans; Huntington Disease - genetics; Huntington Disease - metabolism; Huntington Disease - pathology; Huntington’s; Iron; Iron Compounds - adverse effects; Mice; Mice, Transgenic; Motor Cortex - drug effects; Motor Cortex - metabolism; Motor Cortex - pathology; Neurodegeneration; Neurons - metabolism; Neurons - pathology; Oxidative stress; Oxidative Stress - drug effects; Phenotype; Research Paper; Rotarod Performance Test; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; Stereology
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2015.02.002

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.