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Redox Biol. 2015;4:363-74. doi: 10.1016/j.redox.2015.02.002. Epub 2015 Feb 11.

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

Author information

1
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: kberggre@uwyo.edu.
2
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.
3
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: jfox8@uwyo.edu.
4
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: jmill129@uwyo.edu.
5
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: ldodds917@gmail.com.
6
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: dugas@uw.edu.
7
Department of Veterinary Sciences, University of Wyoming, 1174 Snowy Range Road, Laramie, WY 82070, USA. Electronic address: lvargas1@uwyo.edu.
8
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia.
9
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: irene.volitakis@florey.edu.au.
10
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: blaine.roberts@florey.edu.au.
11
Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3010, Australia. Electronic address: ashleyib@unimelb.edu.au.
12
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.

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.

KEYWORDS:

Gene environment interaction; Huntington’s; Iron; Neurodegeneration; Oxidative stress; Stereology

PMID:
25703232
PMCID:
PMC4348428
DOI:
10.1016/j.redox.2015.02.002
[Indexed for MEDLINE]
Free PMC Article

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