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.

Neonatal Iron Supplementation Induces Striatal Atrophy in Female YAC128 Huntington’s Disease Mice

“…2). This finding corroborates our prior study demonstrating that neonatal, but not adult, iron supplementation potentiates disease in the rapidly progressive R6/2 mouse HD model [16]. The studies support work investigating if iron supplementation in HTT mutation positive infants has a role in potentiating the human disease.…”

“…Significantly increased body weights in HD mice from 3 months of age (not shown) complicates interpretation of these data. In contrast to the neonatal iron study, and in agreement with our prior study in R6/2 HD mice [16], we found no evidence that increased iron intake in adult-life potentiates HD (Figs. 5–7).…”

“…Here we report findings from such studies investigating the effects of elevated iron intake in neonatal and adult-life stage in YAC128 HD mice. Similar to our previous findings [16] we found that iron supplementation in neonatal YAC128 HD mice resulted in potentiation of striatal atrophy while there was no effect of supplementation in adult YAC128 mice.…”

“…Mounted sections were allowed to dry overnight, stained with a 0.5% (w/v) thionin solution then dehydrated and mounted in permount solution. Stereo Investigator Software (MBF Bioscience, Williston, VT) was used to quantify striatal volumes, cell body volumes and neuronal numbers as described previously [16, 22]. Briefly, in a single section at the level of the anterior commissure, the optical fractionator workflow and the nucleator method were used for estimation of neuronal cell body volume.…”

“…To determine if such iron-intake variation may modify HD we previously tested the effect of elevated iron intake during neonatal and adult-life stages in the R6/2 mouse model of HD. We recently reported that iron supplementation in neonatal, but not adult, R6/2 mice potentiates established behavioral, biochemical and morphologic markers of HD [16]. R6/2 HD express the exon-1 fragment of mHTT with 150–180 CAG repeats.…”