Faculty Articles

Brain iron loading impairs DNA methylation and alters GABAergic function in mice.

ISBN or ISSN

1530-6860

Publication Title

The FASEB Journal

Volume

33

Issue

2

Publication Date / Copyright Date

2-1-2019

First Page

2460

Last Page

2471

Publisher

The Federation

Abstract

Iron deficiency is closely associated with altered GABA metabolism and affective behavior. While mutation in the hemochromatosis ( HFE) gene disrupts iron homeostasis and promotes oxidative stress that increases the risk of neurodegeneration, it is largely unknown whether HFE mutation modifies GABAergic homeostasis and emotional behavior. The goal of our study was to investigate the impact of HFE on GABAergic neurochemistry and redox-epigenetic regulation in the brain using H67D HFE-mutant mice that recapitulates the H63D-HFE mutation in humans. H67D mice displayed elevated redox-active iron levels in the brain by 32% compared to age-matched wild-type mice. Moreover, the H67D brain had increased isoprostane and decreased glutathione, indicating elevated oxidative stress. Additionally, the H67D brain had decreased global methylation and attenuated DNA methyltransferase (DNMT) activity. Direct addition of iron to purified DNMT in vitro decreased enzyme activity in a concentration-dependent manner. Last, H67D mice exhibited decreased anxiety-like behavior, which was associated with increased expression of the GABA

Disciplines

Medicine and Health Sciences | Pharmacy and Pharmaceutical Sciences

Keywords

Animals, Brain, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Hemochromatosis Protein, Humans, Iron, Male, Mice, Mice, Inbred C57BL, Mutation, Oxidative Stress, Protein Subunits, Receptors, GABA-A

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