Emerging roles of ER-resident selenoproteins in brain physiology and physiopathology

Abstract

The brain has a very high oxygen consumption rate and is particularly sensitive to oxidative stress. It is also the last organ to suffer from a loss of selenium (Se) in case of deficiency. Se is a crucial trace element present in the form of selenocysteine, the 21st proteinogenic amino acid present in selenoproteins, an essential protein family in the brain that participates in redox signaling. Among the most abundant selenoproteins in the brain are glutathione peroxidase 4 (GPX4), which reduces lipid peroxides and prevents ferroptosis, and selenoproteins W, I, F, K, M, O and T. Remarkably, more than half of them are proteins present in the ER and recent studies have shown their involvement in the maintenance of ER homeostasis, glycoprotein folding and quality control, redox balance, ER stress response signaling pathways and Ca²⁺ homeostasis. However, their molecular functions remain mostly undetermined. The ER is a highly specialized organelle in neurons that maintains the physical continuity of axons over long distances through its continuous distribution from the cell body to the nerve terminals. Alteration of this continuity can lead to degeneration of distal axons and subsequent neuronal death. Elucidation of the function of ER-resident selenoproteins in neuronal pathophysiology may therefore become a new perspective for understanding the pathophysiology of neurological diseases. Here we summarize what is currently known about each of their molecular functions and their impact on the nervous system during development and stress.

Keywords: Brain pathologies; Calcium mobilization; ER protein Folding; Selenium; Thiol redox switch.

Fig. 1

Neuroprotective roles of selenoproteins in the brain The brain has a high concentration of unsaturated fatty acids and weak antioxidant defense mechanisms, making it susceptible to oxidative stress. Selenoproteins are major components of the antioxidant defense strategy in the brain. Se enters the brain primarily as SELENOP, which enables the expression of other selenoproteins by providing Se as Sec [18,38,184]. The major selenoproteins expressed in the brain are listed according to their expression levels in human and mouse brain [51,72]. GPX1 and 4 reduce lipid and hydrogen peroxides [185]. Most other selenoproteins have antioxidant action as well. Those residing in the ER (bold, blue) participate in the maintenance of ER proteostasis and Ca²⁺ homeostasis. Upon protein overload, the UPR is activated, leading to activation of PDI and increased production of ROS, further exacerbating oxidative stress. When cellular production of ROS overwhelms its antioxidant capacity, it leads to a state of oxidative stress, which in turn contributes to activate the NFκB signaling pathways, neuronal cell death and glial reactivity [186,187]. Whereas selenoprotein expression is prominent in neurons and barely detectable in astrocytes, brain injury results in strong upregulation of SELENOS and SELENOT, specifically in reactive astrocytes in mice [69,129]. Oxidative stress and ER stress contributes to the pathogenesis of several human neurological diseases. In this scenario, Se deficiency further increases sensitivity to oxidative stress, and sensitizes to neurodegeneration [54,188].[54,188]. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2

Schematic summary of the different functions performed by the seven ER-resident selenoproteins. Pathologies and cellular dysfunctions associated with each of them are indicated. SELENON is activated by low ER calcium level. This leads to its interaction with SERCA pump and its activation. Its loss of function leads to hypersensibility to ERO1, defect in Ca²⁺ reuptake, and to a disease called SEPN1-related myopathy associated with insulin resistance. SELENOM reduces ROS level in cell culture and is able to interact with Gal1, a lectin with higher affinity for galactose, preventing neurodegeneration and promoting neuroprotection in the brain. Deletion of SELENOM leads to obesity without cognitive impairment. SELENOT deletion from neuronal precursor leads to brain growth retardation associated to high ROS levels, and increased vulnerability to neurodegeneration. It interacts with the OST complex and modulates N-glycosylation. Its inhibition leads to secretion defects and ER stress in endocrine cells. Dio2 catalyzes the deiodination of T4 (3,5,3′,5′-tetraiodothyronine) into T3 (3,5,3′-triiodothyronine). DIO2 in the brain may be a determinant of well-being and neurocognitive function. The Thr92Ala mutation, a well-studied polymorphism present in 12–36% of the population, leads to ER stress and hypothyroidism. This mutation is presumably responsible of a decrease of DIO2 through ubiquitination by E3 ubiquitin ligase and degradation by the proteasome. SELENOS inhibition increase Tau aggregation. It is involved in C99 degradation through its interaction with ERAD complex involved in clearing of misfolded glycoproteins, and its expression correlates with NFTs from post-mortem human brain. SELENOS upregulation can also lead to insulin resistance. SELENOK interacts with SELENOS and ERAD, limiting ER stress. It also interacts with DHHC6, a protein responsible for IP3R palmitoylation, a necessary step for its stabilization. It is believed that this link with Ca²⁺ regulation supports microglial migration and Aβ deposit clearance in AD. SELENOF is a partner of UGGT, a folding sensor of the ER transferring a glucose residue to the A branch of oligomannoses from misfolded glycoproteins to make it join the quality control process. If the protein isn't correctly folded after a few cycles, it will join the ERAD pathway. SELENOF deletion in animal leads to an early age cataract. This could be due to an increase of misfolded protein or to the lack of interaction with RDH11, a protein involved in vitamin A metabolism.