The Function of Selenium in Central Nervous System: Lessons from MsrB1 Knockout Mouse Models

Abstract

MsrB1 used to be named selenoprotein R, for it was first identified as a selenocysteine containing protein by searching for the selenocysteine insert sequence (SECIS) in the human genome. Later, it was found that MsrB1 is homologous to PilB in Neisseria gonorrhoeae, which is a methionine sulfoxide reductase (Msr), specifically reducing L-methionine sulfoxide (L-Met-O) in proteins. In humans and mice, four members constitute the Msr family, which are MsrA, MsrB1, MsrB2, and MsrB3. MsrA can reduce free or protein-containing L-Met-O (S), whereas MsrBs can only function on the L-Met-O (R) epimer in proteins. Though there are isomerases existent that could transfer L-Met-O (S) to L-Met-O (R) and vice-versa, the loss of Msr individually results in different phenotypes in mice models. These observations indicate that the function of one Msr cannot be totally complemented by another. Among the mammalian Msrs, MsrB1 is the only selenocysteine-containing protein, and we recently found that loss of MsrB1 perturbs the synaptic plasticity in mice, along with the astrogliosis in their brains. In this review, we summarized the effects resulting from Msr deficiency and the bioactivity of selenium in the central nervous system, especially those that we learned from the MsrB1 knockout mouse model. We hope it will be helpful in better understanding how the trace element selenium participates in the reduction of L-Met-O and becomes involved in neurobiology.

Keywords: MsrB1; central nervous system; redox; selenium; synaptic plasticity.

Figure 1

Methionine residue can be oxidized into methionine sulfoxide by, e.g., ROS and further oxidized into methionine sulfone by, e.g., performic acid; however, only methionine sulfoxide can be reduced back into methionine by methionine sulfoxide reductase (Msr) in a stereospecific manner.

Figure 2

The interaction of MsrB1 with CaMKIIα and CaMKIIβ demonstrated by yeast two-hybrid screening.

Figure 3

Schematic description of the hypothesis of how MsrB1 is involved in synaptic plasticity. The autophosphorylation of CaMKII could be triggered by Ca²⁺/calmodulin in an excited neuron. However, the overload of Ca²⁺ could induce excitatory toxicity, including the production of ROS by mitochondria, which could further oxidize CaMKII and perturb the phosphorylation of CaMKII. Therefore, synaptic plasticity would be impaired by excessive ROS. Meanwhile, MsrB1 could reduce the oxidized methionine residue in CaMKII and subsequently rescue the synaptic plasticity.