Selenoproteins in Nervous System Development, Function, and Degeneration
The discovery of spontaneous neurological phenotypes in selenoprotein P-deficient (Sepp −/− ) mice marks a turning point in our appreciation of selenium (Se) and selenoproteins within the nervous system. Before, Se was viewed mainly as a cofactor of glutathione peroxidase 1 (GPx1), and feeding animals low Se-containing diets or targeted inactivation of Gpx1 have merely exacerbated neurological damage caused by experimental brain ischemia or exposure to neurotoxins. Case reports on a possible relationship between Se and neurological disease in patients were inspiring and often visionary, but initially failed to provide a solid mechanistic framework to explain the observed phenotypes. Sepp inactivation for the first time provided a tool to experimentally modulate brain Se content and brain selenoprotein expression. Since then a large and still growing number of transgenic mouse models affecting cerebral selenoprotein expression have been analyzed with respect to possible neurological defects. These studies revealed that, apart from more general protective roles during neurodegeneration, many specific developmental processes depend on selenoproteins. Recently, the essential roles of selenoproteins in human neurobiology were supported by the identification of patients carrying mutations in genes involved in selenoprotein biosynthesis. The phenotypic similarities between these patients and transgenic mouse models proved that mice represent a valid model for the study of many aspects of the neurobiology of Se. This chapter will summarize the topic from the perspective of molecular genetics.
KeywordsThyroid Hormone Sensorineural Hearing Loss Neurological Phenotype Buthionine Sulfoximine Movement Phenotype
This work was supported by Deutsche Forschungsgemeinschaft (DFG), Deutscher Akademischer Austauschdienst (DAAD), and Charité-Universitätsmedizin Berlin.
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