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Expression of selenoproteins is widespread in neurons of the central nervous system. There is continuous evidence presented over decades that low levels of selenium or selenoproteins are linked to seizures and epilepsy indicating a failure of the inhibitory system. Many developmental processes in the brain depend on the thyroid hormone T3. T3 levels can be locally increased by the action of iodothyronine deiodinases on the prohormone T4. Since deiodinases are selenoproteins, it is expected that selenoprotein deficiency may affect development of the central nervous system. Studies in genetically modified mice or clinical observations of patients with rare diseases point to a role of selenoproteins in brain development and degeneration. In particular selenoprotein P is central to brain function by virtue of its selenium transport function into and within the brain. We summarize which selenoproteins are essential for the brain, which processes depend on selenoproteins, and what is known about genetic deficiencies of selenoproteins in humans. This review is not intended to cover the potential influence of selenium or selenoproteins on major neurodegenerative disorders in human.

Transporter-dependent steroid hormone uptake into target cells was demonstrated in genetically engineered mice and fruit flies. We hypothesized that mutations in such transporters may cause differences in sex development (DSD) in humans. Exome sequencing was performed in 16 genetically unsolved cases of 46,XY DSD selected from an anonymized collection of 708 lines of genital fibroblasts (GF) that were taken from individuals with incomplete virilization. Selection criteria were based on available biochemical characterization of GF compatible with reduced androgen uptake. Two unrelated individuals were identified with mutations in LDL receptor-related protein 2 (LRP2), a gene previously associated with partial sex steroid insensitivity in mice. Like Lrp2

γ-Secretase is a protease catalysing the proteolysis of type-I membrane proteins usually after precedent ectodomain shedding of the respective protein substrates. Since proteolysis of membrane proteins is involved in fundamental cellular signaling pathways, dysfunction of γ-secretase can have significant impact on cellular metabolism and differentiation. Here, we examined the role of γ-secretase in cellular lipid metabolism using neuronally differentiated human SH-SY5Y cells. The pharmacological inhibition of γ-secretase induced lipid droplet (LD) accumulation. The LD accumulation was significantly attenuated by preventing the accumulation of C-terminal fragment of the amyloid precursor protein (APP-CTF), which is a direct substrate of γ-secretase. Additionally, LD accumulation upon γ-secretase inhibition was not induced in APP-knock out (APP-KO) mouse embryonic fibroblasts (MEFs), suggesting significant involvement of APP-CTF accumulation in LD accumulation upon γ-secretase inhibition. On the other hand, γ-secretase inhibition-dependent cholesterol accumulation was not attenuated by inhibition of APP-CTF accumulation in the differentiated SH-SY5Y cells nor in APP-KO MEFs. These results suggest that γ-secretase inhibition can induce accumulation of LD and cholesterol differentially via APP-CTF accumulation.

In the brain, the neurotrophin Nerve growth factor (NGF) regulates not only neuronal survival and differentiation, but also glial and microglial functions and neuroinflammation. NGF is known to regulate oligodendrogenesis, reducing myelination in the central nervous system (CNS). In this study, we found that NGF controls oligodendrogenesis by modulating the levels of miR-219a-5p, a well-known positive regulator of oligodendrocyte differentiation. We exploited an NGF-deprivation mouse model, the AD11 mice, in which the postnatal expression of an anti-NGF antibody leads to NGF neutralization and progressive neurodegeneration. Notably, we found that these mice also display increased myelination. A microRNA profiling of AD11 brain samples and qRT-PCR analyses revealed that NGF deprivation leads to an increase of miR-219a-5p levels in hippocampus and cortex and a corresponding down-regulation of its predicted targets. Neurospheres isolated from the hippocampus of AD11 mice give rise to more oligodendrocytes and this process is dependent on miR-219a-5p, as shown by decoy-mediated inhibition of this microRNA. Moreover, treatment of AD11 neurospheres with NGF inhibits miR-219a-5p up-regulation and, consequently, oligodendrocyte differentiation, while anti-NGF treatment of wild type (WT) oligodendrocyte progenitors increases miR-219a-5p expression and the number of mature cells. Overall, this study indicates that NGF inhibits oligodendrogenesis and myelination by down-regulating miR-219a-5p levels, suggesting a novel molecular circuitry that can be exploited for the discovery of new effectors for remyelination in human demyelinating diseases, such as Multiple Sclerosis.

Inhibition of the Alzheimer associated γ-secretase impairs the regulation of cellular lipid droplet homeostasis., Presenilins (PS) are the catalytic components of γ-secretase complexes that mediate intramembrane proteolysis. Mutations in the PS genes are a major cause of familial early-onset Alzheimer disease and affect the cleavage of the amyloid precursor protein, thereby altering the production of the amyloid β-peptide. However, multiple additional protein substrates have been identified, suggesting pleiotropic functions of γ-secretase. Here, we demonstrate that inhibition of γ-secretase causes dysregulation of cellular lipid homeostasis, including up-regulation of liver X receptors, and complex changes in the cellular lipid composition. Genetic and pharmacological inhibition of γsecretase leads to strong accumulation of cytoplasmic lipid droplets, associated with increased levels of acylglycerols, but lowered cholesteryl esters. Furthermore, accumulation of lipid droplets was augmented by increasing levels of amyloid precursor protein C-terminal fragments, indicating a critical involvement of this γ-secretase substrate. Together, these data provide a mechanism that functionally connects γ-secretase activity to cellular lipid metabolism. These effects were also observed in human astrocytic cells, indicating an important function of γ-secretase in cells critical for lipid homeostasis in the brain.