Utilization of selenium in the mouse brain : implications for neurological disease

Abstract

Selenium is a chemical element that is an essential micronutrient associated with various aspects of human health. The biochemical activity of selenium is mediated by proteins, which incorporate it into the amino acid selenocysteine (Sec). There are 25 genes in humans encoding Sec-containing selenoproteins. The functionally characterized selenoproteins are oxidoreductase enzymes involved in cellular oxidation-reduction reactions. Most selenoproteins are expressed in the mammalian brain, and dietary selenium deficiency causes preferential retention in brain relative to other body organs. Further, dietary selenium deficiency and specific selenoproteins are associated with various brain diseases. Mouse models have been extensively used to study the function and handling of selenium in mammals. Genetic deletion of a Sec-rich protein in mice causes brain selenium deficiency, neurodegeneration and neurological impairment, and disruption of a phospholipid hydroperoxidase selenoenzyme causes rapid neurodegeneration. Therefore, selenoprotein expression and function promotes a healthy nervous system. However, selenium metabolism and the function of several selenoproteins in brain are not clearly defined. The overall purpose of this work is to clarify the function and utilization of selenium in the mammalian brain, to reveal implications for developmental and neurological diseases. The goal of these studies is to investigate changes in brain function and selenoprotein expression under conditions of altered selenium metabolism in mice. The research presented in this dissertation covers three major topics that are separated into chapters. To investigate selenium distribution in the brain, the neurological consequences of disrupting selenium transport and recycling in mice are assessed and compared. Disruption of selenium transport caused more profound neurological consequences than disruption of selenium recycling. To investigate potential functions of selenium in the nervous system, select selenoproteins were examined for cellular and subcellular expression in cells and brain tissue from transgenic and control mice. Select selenoproteins and synthesis factors were observed at synapses, suggesting localized expression and physiological relevance. To investigate a potential interaction between selenium and methamphetamine, expression profiling of selenoproteins in mouse brain after exposure to methamphetamine is described. Selenoprotein synthesis was adversely affected by methamphetamine administration in mice. These results confirm the importance of selenium in the mammalian brain.