Brainstem Axonal Degeneration in Mice with Deletion of Selenoprotein P

Abstract

Selenoprotein P is an abundant extracellular protein that is expressed in liver, brain, and other tissues. Studies in mice with the selenoprotein P gene deleted (Sepp-/- mice) have implicated the protein in maintaining brain selenium. Sepp-/- mice fed a normal or low selenium diet develop severe motor impairment and die, but Sepp-/- mice fed a high selenium diet remain clinically unimpaired. As an initial step to evaluate the effect of selenoprotein P deletion on central nervous system architecture, the brains and cervical spinal cords of Sepp-/- and Sepp+/+ mice fed low or high selenium diets were examined by light and electron microscopy. Brains of Sepp-/- mice demonstrated no gross abnormalities. At the light microscopic level, however, Sepp-/- mice fed either the selenium deficient diet or the high selenium diet had enlarged dystrophic axons and degenerated axons in their brainstems and cervical spinal cords. No axonal lesions were observed in the Sepp+/+ mice fed either diet. Electron microscopy demonstrated that the enlarged axons in the Sepp-/- mice were packed with organelles, suggesting a deficit in fast axonal transport. The similar severity of axonal lesions observed in Sepp-/- mice fed the 2 diets suggests that axonal dystrophy is a common phenotype for deletion of selenoprotein P regardless of selenium intake and that additional studies will be required to determine the pathogenesis of the neurological signs and mortality observed in Sepp-/- mice fed a low selenium diet.

Association of Selenoprotein P with Alzheimer's Pathology in Human Cortex

“…Normal function can be rescued with a diet supplemented with high levels of Se [24]. Although Se supplemented mice survive and appear normal, they exhibit severe brain stem axonal degeneration [30]. Recent evidence suggests SelP is transported into brain by the apolipoprotein E (ApoE) receptor, ApoER2.…”

Role of Selenium on Calcium Signaling and Oxidative Stress-induced Molecular Pathways in Epilepsy

“…The latter are NADPH-dependent enzymes that convert oxidized thioredoxin back to the dithiol form. The plasma protein selenoprotein P is important in delivering selenium to the brain; mice lacking this protein die with severe degeneration of motor neurons unless their diet is enriched with selenium [34].…”

Progression of neurodegeneration and morphologic changes in the brains of juvenile mice with selenoprotein P deleted

“…Sepp1 delivers selenium to brain and testes through interaction with the apolipoprotein E receptor 2 (apoER2), and once in the cells, selenium is then incorporated into selenoproteins during their synthesis (Burk et al 2005; Burk et al 2009). Deletion of Sepp1 in mice decreases brain selenium levels and feeding these mice a selenium-deficient diet results in severe neurological impairments and death (Hill et al 2004; Valentine et al 2005; Valentine et al 2008). In our previous studies, we identified extensive axonal degeneration in the brainstem and thalamus of Sepp1 −/− mice fed a selenium-deficient diet for 14 days (Valentine et al 2008).…”