Siglecs in Brain Function and Neurological Disorders

Abstract

Siglecs (Sialic acid-binding immunoglobulin-type lectins) are a I-type lectin that typically binds sialic acid. Siglecs are predominantly expressed in immune cells and generate activating or inhibitory signals. They are also shown to be expressed on the surface of cells in the nervous system and have been shown to play central roles in neuroinflammation. There has been a plethora of reviews outlining the studies pertaining to Siglecs in immune cells. However, this review aims to compile the articles on the role of Siglecs in brain function and neurological disorders. In humans, the most abundant Siglecs are CD33 (Siglec-3), Siglec-4 (myelin-associated glycoprotein/MAG), and Siglec-11, Whereas in mice the most abundant are Siglec-1 (sialoadhesin), Siglec-2 (CD22), Siglec-E, Siglec-F, and Siglec-H. This review is divided into three parts. Firstly, we discuss the general biological aspects of Siglecs that are expressed in nervous tissue. Secondly, we discuss about the role of Siglecs in brain function and molecular mechanism for their function. Finally, we collate the available information on Siglecs and neurological disorders. It is intriguing to study this family of proteins in neurological disorders because they carry immunoinhibitory and immunoactivating motifs that can be vital in neuroinflammation.

Keywords: Alzheimer’s disease; ITAM; ITIM; Siglecs; brain; ganglioside; microglia; multiple sclerosis; myelin; neurological disorder; sialic acid.

Figure 1

The human Siglec family receptors. The human Siglec receptors are expressed on the immune cells and have Ig-like extracellular domain. They carry one extracellular V-set domain that binds with sialic acid ligands. Beneath V-set domain these receptors carry different numbers of C2-set domains. Siglec-3 and Siglec-15 have only one C2-set domain while Siglec-1 has 16 C2-set domains. As an exception, Siglec-XII has two V-set domains but both of them do not have critical arginine and does not bind with sialic acid ligand. Most of the Siglecs have ITIM and ITIM-like domain that facilitates inhibitory signal to the cells. Siglec-14, -15, and -16 have positively charged residue in the transmembrane domain that recruit Dap12 and facilitate activating signal to the cells.

Figure 2

The mouse Siglec family receptors. In mouse and human, there are some Siglec receptors that are conserved such as Siglec-1, Siglec-2, and MAG while others are rapidly evolving and do not have true ortholog between human and mouse. These rapidly evolving Siglecs in mouse are CD33, Siglec-E, -F, -G, and -H. The outermost N terminal domain has V-set domain and below the V-set domain has C2-set domains similar to human Siglecs. In the intracellular domain there is ITIM and ITIM-like motifs.