Impact of structural aberrancy of polysialic acid and its synthetic enzyme ST8SIA2 in schizophrenia

Abstract

Psychiatric disorders are a group of human diseases that impair higher cognitive functions. Whole-genomic analyses have recently identified susceptibility genes for several psychiatric disorders, including schizophrenia. Among the genes reported to be involved in psychiatric disorders, a gene encoding a polysialyltransferase involved in the biosynthesis of polysialic acid (polySia or PSA) on cell surfaces has attracted attention for its potential role in emotion, learning, memory, circadian rhythm, and behaviors. PolySia is a unique polymer that spatio-temporally modifies neural cell adhesion molecule (NCAM) and is predominantly found in embryonic brains, although it persists in areas of the adult brain where neural plasticity, remodeling of neural connections, or neural generation is ongoing, such as the hippocampus, subventricular zone (SVZ), thalamus, prefrontal cortex, and amygdala. PolySia is thought to be involved in the regulation of cell-cell interactions; however, recent evidence suggests that it is also involved in the functional regulation of ion channels and neurologically active molecules, such as Brain-derived neurotrophic factor (BDNF), FGF2, and dopamine (DA) that are deeply involved in psychiatric disorders. In this review, the possible involvement of polysialyltransferase (ST8SIA2/ST8SiaII/STX/Siat8B) and its enzymatic product, polySia, in schizophrenia is discussed.

Keywords: BDNF; NCAM; ST8SIA2; dopamine; polysialic acid; polysialyltransferase; psychiatric disorder; schizophrenia.

Figure 1

Structures of polySia, polySia-NCAM, and polySia-synCAM. (A) α2-8linked polySia structure. R = -NHCOCH₃, Neu5Ac; -NHCOCH₂OH, Neu5Gc, -OH, KDN. In the brain, polySia is polyNeu5Ac. (B) Molecular modeling of polySia (DP = 12). The polySia structure is linked to Gal at the C3-position. Calculated α2,8-linked dodecaNeu5Ac-Gal structure is shown as space-filling models. The MOE program was used for the construction and calculation of the energies of α2,8-linked polySia. (C) polySia-NCAM-180 and polySia-synCAM-1. Left panel, NCAM-180. NCAM has five immunoglobulin domains (IgI~IgV) and two fibronectin type-III (FN_III) domains in its extracellular domain. In the IgV domain, two of the three N-glycosylation sites (triangle) are polysialylated and are indicated by black circles (sialic acid). Right panel, SynCAM-1. SynCAM-1 has three Ig domains. In the IgI domain, one of the three N-glycosylation sites (triangle) is occupied by polySia which is indicated by black circles (sialic acid).

Figure 2

Biosynthesis of polySia and schematic structure of ST8SIA2. (A) Mono and di/oligo/polysialylation pathway on the terminal Gal residue of N-glycan chains. Asialo-glycoprotein is mono-sialylated by the action of ST3/6GAL. ST8SIA2, ST8SIA4, and/or ST8SIA2/4 can synthesize polySia chains on the monosialyl residue, particularly on NCAM. (B) Schematic representation of the protein structure of ST8SIA2. ST8SIA2 consists of a short cytoplasmic region (CR) connected to a transmembrane (TM) region, which is followed by an intraluminal region consisting of a stem region and catalytic domain. In the catalytic domain, SML (Sialyl Motif Large), SMS (Small), motif III, and SMVS (Very Short) are present. Two additional regions have been newly characterized: a polybasic polysialyltransferase domain (PSTD) and a polybasic motif named the polybasic region (PBR). C, cysteine residues; diamonds, N-glycosylation site; open diamonds, autopolysialylation sites (Asn 89, 219, and 234) of six N-linked glycans; arrowheads, exon junction.

Figure 3

Functions of polySia. (A) Anti-adhesive effect. PolySia-NCAM imparts a repulsive field on the cell surface due to the large volume of polySia (shown in gray) to negatively regulate cell-cell interactions. (B) Regulation of ion transport. The influx and efflux of ions, such as Ca²⁺ are regulated by polySia. PolySia on NCAM interacts with Ca²⁺ channels, such as AMPA receptors, and regulates their opening and closing, by which polySia controls ion transport. (C) Retention or reservoir of biologically active molecules. PolySia on NCAM directly binds to various types of biologically active molecules involved in neural function, such as neurotrophins, neurotransmitters, and growth factors. PolySia-NCAM provides attractive fields that regulate their extracellular concentrations and signaling modes.

Figure 4

Proposed mechanism for the retention and release of biologically active molecules by polySia. Middle panel, PolySia captures biologically active molecules by direct binding. The retained molecules are released by one of several ways, as shown in the left and right panels. Left panel, Specific receptor-mediated release mechanism-1 (Affinity). In this example, brain-derived neurotrophic factor (BDNF) in a complex with polySia migrates to the BDNF receptors, TrkB or p75NTR, based on differences in the affinity between BDNF, the receptors, and polySia. Right panel, Specific receptor-mediated release mechanism-1 (Co-receptor). In the case of fibroblast growth factor 2 (FGF2), polySia does not release FGF2 from the FGF2-polySia complex to the FGF receptor (FGFR). Notably, FGF2 in the FGF2-polySia complex can migrate to heparan sulfate (HS) to form a FGF2-HS complex, which can then bind to FGFR as a ternary complex to enhance FGF signaling. Therefore, polySia regulates FGF2 signaling by passing FGF2 to HS and finally to FGFR.

Figure 5

Disease risk depends on the quantity and quality of polySia. The quantity and quality (degree of polymerization) of polySia may differ from person to person, particularly for patients suffering from psychiatric disorders or other neurodegenerative diseases. Direct and indirect lines of evidence show that quantity and quality of polySia on NCAM are critically important for normal brain functions. Hyper- or hypo-polysialylation of NCAM might lead to the impairment of brain function through the stimulation or repression of dopamine-, BDNF- and FGF2-mediated signaling.