New Functions of Polysialic Acid and Its Relationship to Schizophrenia

Abstract

Polysialic acid (polySia), particularly α2,8-linked polyNeu5Ac (DP=8∼400), is a unique polymer that spatio-temporally modifies neural cell adhesion molecule (NCAM), predominantly in embryonic brains. PolySia is considered to function as a negative regulator of adhesion between cells, and between cells and extracellular matrix due to its extremely polyanionic nature and steric hindrance. Through its anti-adhesive property and spatio-temporal expression, polySia is involved in cell migration, neural outgrowth, axonal guidance, synaptic plasticity, and the development of normal neural circuits and neurogenesis. Due to improvements of polySia-detection methods, it has been shown that polySia expression persists in the hippocampus and olfactory bulb of adults, where neurogenesis is ongoing; however, the functions of polySia, particularly in adult brains, remain incompletely resolved. Recently, we demonstrated that polySia functions not only as an anti-adhesive molecule, but also as a reservoir for specific bioactive molecules, such as neurotrophic factors, neurotransmitters, and growth factors, which regulate neural function. In addition, studies have revealed that the enzymatic activity of STX, which is involved in the synthesis of polySia, derived from schizophrenic patient is low and that the product of the enzyme, polySia on NCAM is impaired with respect to both quantity and quality. Notably, impaired polySia-NCAM cannot effectively retain bioactive molecules, including BDNF, dopamine, and FGF2. Taken together, the impairment of polySia might influence the retention function of polySia and lead to the development of psychiatric disorders, such as schizophrenia, which are reported to express either lower or elevated amounts of polySia compared with normal brains.