Structural and Functional Impairments of Polysialic Acid by a Mutated Polysialyltransferase Found in Schizophrenia

Abstract

Polysialic acid (polySia), a unique acidic glycan modifying neural cell adhesion molecule (NCAM), is known to regulate embryonic neural development and adult brain functions. Polysialyltransferase STX is responsible for the synthesis of polySia, and two single nucleotide polymorphisms (SNPs) of the coding region of STX are reported from schizophrenic patients: SNP7 and SNP9, respectively, giving STX(G421A) with E141K and STX(C621G) with silent mutations. In this study, we focused on these mutations and a binding activity of polySia to neural materials, such as brain-derived neurotrophic factor (BDNF). Here we describe three new findings. First, STX(G421A) shows a dramatic decrease in polySia synthetic activity on NCAM, whereas STX(C621G) does not. The STX(G421A)-derived polySia-NCAM contains a lower amount of polySia with a shorter chain length. Second, polySia shows a dopamine (DA) binding activity, which is a new function of polySia as revealed by frontal affinity chromatography for measuring the polySia-neurotransmitter interactions. Interestingly, the STX(G421A)-derived polySia-NCAM completely loses the DA binding activity, whereas it greatly diminishes but does not lose the BDNF binding activity. Third, an impairment of the polySia structure with an endosialidase modulates the DA-mediated Akt signaling. Taken together, impairment of the amount and quality of polySia may be involved in psychiatric disorders through impaired binding to BDNF and DA, which are deeply involved in schizophrenia and other psychiatric disorders, such as depression and bipolar disorder.

Sequences Prior to Conserved Catalytic Motifs of Polysialyltransferase ST8Sia IV Are Required for Substrate Recognition

“…This leads to an increase in intermembrane repulsion (25) and pre-vents both NCAM-dependent and NCAM-independent cellcell adhesion (26,27). In addition, polySia was recently demonstrated to bind and sequester neurotrophic factors and neurotransmitters and this ability could impact signaling and contribute to its various roles during development and in the adult animal (28,29).…”

New Functions of Polysialic Acid and Its Relationship to Schizophrenia

“…In addition, we are analyzing the releasing mechanism of polySia. In this section, we will introduce brainderived neurotrophic factor (BDNF) (32,33), catecholamines (dopamine) (34,35), and a growth factor (FGF2) (36) as polySia-interacting molecules. D-1.…”

“…The binding between polySia and catecholamine neurotransmitters has been demonstrated by frontal affinity chromatography (FAC) (34,35). Although FAC is a wellknown method to analyze interactions between glycans and lectins, these studies are the first application of FAC to analyze the interactions between glycans and small molecules.…”

“…In addition, in the course of development and improvement of detection methods for polySia, several new polySia-containing glycoproteins have been discovered. The application of these detection methods to the study of polySia-related interactions (32,34,35) has revealed novel functions of polySia. In this mini-review, we will introduce the newly discovered functions of polySia and discuss the relationships between polySia and psychiatric disorders, particularly schizophrenia, which have been reported to date.…”

Sialidase NEU4 Hydrolyzes Polysialic Acids of Neural Cell Adhesion Molecules and Negatively Regulates Neurite Formation by Hippocampal Neurons

“…Because of its polyanionic structure and large hydrated volume (2,3), modulation of polySia levels influences a wide range of structural changes in cell position and shape in the nervous system. Numerous studies have provided evidence for crucial functions of polySia on NCAM (4,5), especially with observation of NCAM and/or polysialyltransferase-deficient mice (6 -10). In fact, polySia has been implicated in synaptic plasticity, neuronal differentiation, and cell migration (1,11,12).…”