Neuronal and ependymal expression of selenoprotein P in the human brain

Abstract

Selenoprotein P (SePP) is central to selenium (Se) metabolism in the mammalian organism. Human SePP contains 10 Se atoms that are covalent constituents of the polypeptide chain incorporated as the rare amino acid selenocysteine (Sec). Since hepatocytes secrete SePP into plasma, SePP is commonly regarded as a Se transport protein, although SePP mRNA is expressed in many organs. Gene targeting of SePP in mice leads to neurological dysfunction resulting from Se deficiency and associated reduction of selenoenzyme activities in the brain. However, more recent data revealed that isolated hepatic SePP deficiency does not alter brain Se levels, suggesting a role for SePP locally expressed in the brain. Some of the best characterized and most abundant selenoenzymes, glutathione peroxidases, thioredoxin reductases, and methionine sulfoxide reductase B, play major roles in the cellular defense against reactive oxygen species. Therefore, it was hypothesized that reduced brain Se bioavailability may be involved in the pathogenesis of neurodegenerative disease and normal ageing. We present evidence that human CSF contains SePP and that the human brain expresses SePP mRNA. Moreover, SePP-like immunoreactivity localizes to neurons and ependymal cells and thus appears strategically situated for maintenance and control of Se-dependent anti-oxidative defense systems.

Comparative Analysis of Selenocysteine Machinery and Selenoproteome Gene Expression in Mouse Brain Identifies Neurons as Key Functional Sites of Selenium in Mammals

“…4). SelP was detected previously in human cerebrospinal fluid (24). Here, SelP expression was also detected at elevated levels, suggesting secretion of SelP into mouse cerebrospinal fluid.…”

“…Previously, it was found to be highly expressed in olfactory bulb and cerebellum (22,23). SelP-like immunoreactivity was detected on neurons and some white matter tracts (24). Given its role as a Se carrier, its expression in glial cells would help store Se in the brain and also provide it to neurons for selenoprotein biosynthesis.…”

“…), studies on selenoprotein expression and the roles of these proteins in brain function lagged behind those in other organs, such as liver and kidney. With the exception of GPx1 (21), SelW, SelP (22)(23)(24), and GPx4 (25), systematic expression data in the brain for selenoproteins are not available. Expression of Sec biosynthesis and insertion machinery, such as Sec synthase, SECIS-binding protein 2 (SBP2), and O-phosphoseryl-tRNA [Ser]Sec kinase (PSTK) also has not been examined.…”

Mice Lacking Selenoprotein P and Selenocysteine Lyase Exhibit Severe Neurological Dysfunction, Neurodegeneration, and Audiogenic Seizures

“…Furthermore, liver-specific ablation of selenoprotein synthesis does not reduce brain GPx activity or induce neurological dysfunction, indicating that the brain is not dependent on Sepp1 derived from the liver (22). These findings, along with studies showing that Sepp1 is expressed in the brain (23,24), suggest a distinct pool of Sepp1 acts locally within the brain. Scly has been proposed to act in unison with Sepp1 to maintain brain selenoprotein levels by decomposing Sepp1-derived selenocysteine and allowing it to be recycled for selenoprotein synthesis (8,22).…”

Does Inorganic Mercury Play a Role in Alzheimer's Disease? A Systematic Review and an Integrated Molecular Mechanism

“…In the brain, a remarkably high level of SelP is found in ependymal cells [145], whose asymmetric division gives rise to neural stem cells in the subventricular zone and subgranular layer [146,147]. Accordingly, ependymal cells have the highest level of glutathione, more than 10-fold higher than neurons, and 3-fold higher than astrocytes [148].…”