Abstract
The neural cell adhesion molecule (NCAM) is modified by polysialic acid (polySia or PSA) in embryonic brains. In adult brains, polySia modification of NCAM is only observed in restricted areas where neural plasticity, remodeling of neural connections, or neural generation is ongoing although the amount of NCAM remains unchanged. Impairments of the polySia-expression and several single nucleotide polymorphisms (SNPs) of the polysialyltransferase (polyST) ST8SIA2 gene are reported to be associated with schizophrenia and bipolar disorder. Chlorpromazine (CPZ) is well-known as an agent for treating schizophrenia, and our hypothesis is that CPZ may affect the polySia expression or the gene expression of polySTs or NCAM. To test this hypothesis, we analyzed the effects of CPZ on the expression of polySia-NCAM on human neuroblastoma cell line, IMR-32 cells, by immunochemical and chemical methods. Interestingly, the cell surface expression of polySia, especially those with lower chain lengths, was significantly increased on the CPZ-treated cells, while mRNAs for polySTs and NCAM, and the amounts of total polySia-NCAM remained unchanged. The addition of brefeldin A, an inhibitor of endocytosis, suppressed the CPZ-induced cell surface polySia expression. In addition, polySia-NCAM was also observed in the vesicle compartment inside the cell. All these data suggest that the level of cell surface expression of polySia in IMR-32 is highly regulated and that CPZ changes the rate of the recycling of polySia-NCAM, leading to the up-regulation of polySia-NCAM on the cell surface. We also analyzed the effect of CPZ on polySia-expression in various brain regions in adult mice and found that CPZ only influenced the total amounts of polySia-NCAM in prefrontal cortex. These results suggest a brain-region-specific effect of CPZ on the expression of total polySia in mouse brain. Collectively, anti-schizophrenia agent CPZ consistently up-regulates the expression polySia at both cellular and animal levels.
Highlights
The polysialic acid is a linear homopolymer of the sialic acid (Sia) with the degree of polymerization (DP) that varies from 8 to 400 Sia residues [1,2]
We examined the polySia-expression before and after administering CPZ on the cell surface of cells of the human neuroblastoma cell line IMR-32, which is used as a model human neuronal cell line [36,37]
The increased expression of polySia-neural cell adhesion molecule (NCAM) on the cell surface after CPZ addition was observed in SK-N-SH, which is another human neuroblastoma cell line (Figure 1D)
Summary
The polysialic acid (polySia/PSA) is a linear homopolymer of the sialic acid (Sia) with the degree of polymerization (DP) that varies from 8 to 400 Sia residues [1,2]. The majority of polySia is expressed on the neural cell adhesion molecule (NCAM) in embryonic brain, while it almost disappears in the adult brain. PolySia on NCAM is considered as an anti-adhesive molecule that repulses cell-cell interactions due to its physical properties [4]. Through its anti-adhesive effects on cell-cell interactions, polySia has been considered to be involved in the regulation of neuronal functions [3]. There have been several reports on the abnormal expression of polySia in diseases such as schizophrenia [10,11] and various cancers [2]. The polySia biosynthesizing enzyme, ST8SIA2 (STX, siat8b), has been reported to have some association with schizophrenia [8,12,13], bipolar disorder [14], and small cell lung cancer [15]
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