Gene expression in the brain of mutant mouse models of human iron overload

Acikyol, Bulent

Title: Gene expression in the brain of mutant mouse models of human iron overload
Creator: Acikyol, Bulent
Relation: University of Newcastle Research Higher Degree Thesis
Resource Type: thesis
Date: 2014
Description: Masters Research - Master of Philosophy (MPhil)
Description: Iron has vital roles in the body, including oxygen transport and storage through haemoglobin and myoglobin. Iron has also essential roles in brain functions (e.g. neurotransmitter synthesis, myelination) but too little or too much iron can be detrimental to health. Mutations in transferrin receptor 2 (TFR2) gene can cause the disorder hemochromatosis which is characterised by excessive iron accumulation in the liver and other peripheral organs. There is rebate regarding the effects of hemochromatosis on the brain as it has traditionally been believed that blood-brain barrier protects the brain against the aberrant accumulation of the iron from the blood. However genetic mutations that interfere with iron homeostasis could have effects on the brain’s internal iron handling mechanisms, independent of iron status in the periphery. In this project, existing microarray data for Tfr2^mut mice on an AKR background, and age- and gender-matched wildtype (wt) AKR control mice, were first analysed to find expression changes in iron-related genes, genes previously found by our laboratory to show expression changes in the Hfe^-/- mouse brain and dietary iron-supplemented mouse brain and genes that show expression changes in the Tfr2^mut mice but not the other models. Expression changes in genes of interest were then investigated by real time RT-PCR. Changes in the iron storage protein ferritin were also investigated by Western immunoblotting. In addition, sets of differentially expressed genes related to particular biological pathways were determined using the online bioinformatic tool the Database for Annotation, Visualization and Integrated Discovery (DAVID).The Tfr2^mut mouse model used in this study showed significantly increase liver iron levels however, brain non-haem iron or total iron levels did not differ significantly relative to control AKR mice. The increase was of similar magnitude to that previously observed in male mice in two other AKR mouse models of iron loading, dietary iron-supplemented mice. In view of the considerable number of differentially-expressed genes in the Tfr2^mut mouse brain, there were few expression changes for genes directly related to iron metabolism and homeostasis. Instead, expression changes were observed for genes involved in important brain-specific functions, such as LTD and LTP, as well as genes involved in brain diseases. Some of the genes with altered expression in the brain of Tfr2^mut mice have been shown previously to be affected by HFE dysfunction or dietary iron supplementation, whereas others were specific to the Tfr2^mut mice. The findings presented in this research provide support for previous studies from our research group, using dietary iron-supplemented and Hfe^-/- mice, which suggest the brain is not fully protected in haemochromatosis. This is likely to have important implications for brain function in haemochromatosis patients or people with other forms of systemic iron overload. The findings also suggest Tfr2 mutations have important effects on the brain transcriptome. The identification of perturbation for specific transcripts and molecular systems, such as LTD, might help explain neurologic symptoms reported for some haemochromatosis patients.
Subject: iron; brain; hemochromatosis; transferrin receptor 2; microarray
Identifier: http://hdl.handle.net/1959.13/1042269
Identifier: uon:14032
Language: eng
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