ABSTRACT
Selenium is an essential trace element that is co-translationally incorporated into selenoproteins in the form of the 21st amino acid, selenocysteine. This class of proteins largely functions in oxidation-reduction reactions and is critically involved in maintaining proper redox balance essential to health. Selenoprotein M (SelM) is a thioredoxin-like endoplasmic reticulum-resident protein that is highly expressed in the brain and possesses neuroprotective properties. In this study, we first assessed the regional pattern of SelM expression in the mouse brain to provide insights into the potential functional implications of this protein in physiology and behavior. Next, we generated transgenic mice with a targeted deletion of the SelM gene and subjected them to a battery of neurobehavioral tests to evaluate motor coordination, locomotion, and cognitive function in comparison with wild-type controls. Finally, these mice were tested for several measures of metabolic function and body composition. Our results show that SelM knock-out (KO) mice display no deficits in measures of motor coordination and cognitive function but exhibit increased weight gain, elevated white adipose tissue deposition, and diminished hypothalamic leptin sensitivity. These findings suggest that SelM plays an important role in the regulation of body weight and energy metabolism.
Subject(s)
Cognition , Energy Metabolism , Gene Deletion , Hypothalamus/metabolism , Nerve Tissue Proteins/metabolism , Obesity/metabolism , Selenoproteins/metabolism , Animals , Behavior, Animal , Body Weight/genetics , Hypothalamus/pathology , Hypothalamus/physiopathology , Leptin/genetics , Leptin/metabolism , Locomotion/genetics , Mice , Mice, Knockout , Nerve Tissue Proteins/genetics , Obesity/genetics , Obesity/pathology , Obesity/physiopathology , Selenoproteins/geneticsABSTRACT
Selenoproteins contain the trace element selenium incorporated as selenocysteine, the 21st amino acid. Some members of the selenoprotein family, such as the glutathione peroxidases, have well-characterized antioxidant activity, functioning in enzymatic breakdown of hydroperoxides to protect cells against oxidative stress. However, the functions of many of the 25 human selenoproteins, including the brain-enriched selenoprotein M, are unknown. We investigated selenoprotein M function by manipulating expression in murine hippocampal HT22 cells, cerebellar astrocyte C8-D1A cells, and primary neuronal cultures. Overexpression of the protein resulted in a reduction in reactive oxygen species and apoptotic cell death in response to oxidative challenge with hydrogen peroxide. In contrast, knock-down of selenoprotein M using shRNA in primary neuronal cultures caused apoptotic cell death comparable to levels resulting from addition of hydrogen peroxide. Calcium measurements with the indicator cameleon demonstrated that overexpression of selenoprotein M decreased calcium influx in response to hydrogen peroxide. Additionally, knock-down of selenoprotein M expression in cortical cultures caused higher baseline levels of cytosolic calcium than in control cells. These results suggest that selenoprotein M may have an important role in protecting against oxidative damage in the brain and may potentially function in calcium regulation.
Subject(s)
Calcium/metabolism , Cytosol/metabolism , Neuroprotective Agents/metabolism , Selenoproteins/metabolism , Animals , Astrocytes/cytology , Astrocytes/metabolism , Calcium-Binding Proteins/metabolism , Cell Line , Cells, Cultured , Gene Knockdown Techniques , Humans , Hydrogen Peroxide/metabolism , Luminescent Proteins/metabolism , Mice , Neurons/cytology , Neurons/metabolism , Oxidants/metabolism , Oxidation-Reduction , Oxidative Stress , Reactive Oxygen Species/metabolism , Selenium/metabolism , Selenoproteins/geneticsABSTRACT
Selenoproteins are proteins containing selenium in the form of the 21st amino acid, selenocysteine. Members of this protein family have many diverse functions, but their synthesis is dependent on a common set of cofactors and on dietary selenium. Although the functions of many selenoproteins are unknown, several disorders involving changes in selenoprotein structure, activity or expression have been reported. Selenium deficiency and mutations or polymorphisms in selenoprotein genes and synthesis cofactors are implicated in a variety of diseases, including muscle and cardiovascular disorders, immune dysfunction, cancer, neurological disorders and endocrine function. Members of this unusual family of proteins have roles in a variety of cell processes and diseases.