Effect of Transition Metals on Polysialic Acid Structure and Functions
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Abstract Polysialic acid (PSA) is one of the most abundant glycopolymer present in embryonic brain, and it is known to be involved in key roles such as plasticity in the central nervous system, cell adhesion, migration and localization of neurotrophins. However, in adult brain, its expression is quite low. The exception to this is in Alzheimer′s disease (AD) brain, where significantly increased levels of polysilylated neural cell adhesion molecule (PSA‐NCAM) have been reported. Here, we confirm the role of PSA as a metal chelator, allowing it to decrease cytotoxicity caused by high levels of transition metals, commonly found in AD brain, and as a regulator of cell behavior. UV‐visible (UV‐vis) and circular dichroism (CD) spectroscopy, atomic force microscopy (AFM), and isothermal titration calorimetry (ITC) techniques were used to investigate the assembly of PSA–metals complexes. These PSA–metal complexes exhibited less toxicity compared to free metal ions, and in particular, the PSA–Cu 2+ complex synergistically promoted neurite outgrowth in PC12 cells.Keywords:
Polysialic acid
Isothermal Titration Calorimetry
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The neural cell adhesion molecule NCAM is a cell surface glycoprotein of the immunoglobulin superfamily and is widely expressed in tumours of neuroectodermal origin such as neuroblastoma. NCAM can be decorated by the carbohydrate polymer polysialic acid (polySia), which attenuates NCAM-mediated cell adhesion and increases cellular motility. The key enzymes in the biosynthesis of polySia are the two polysialyltransferases ST8SiaII and ST8SiaIV. In the present study, expression of NCAM, polySia-NCAM, ST8SiaII and ST8SiaIV was investigated in five human neuroblastoma cell lines before and after xenografting into SCID mice by immunohistochemistry, Western blot analysis and real-time PCR. Results were correlated with the metastatic potential. In vitro, three cell lines (LAN-1, LAN-5 and SH-SY5Y) were positive for polySia attached to the transmembrane isoforms NCAM-140 and NCAM-180, whereas Kelly and SK-N-SH cells were negative for NCAM and polySia. In the presence of NCAM, the level of polySia correlated with the amount of polysialyltransferase transcripts, which were highest in LAN-1, LAN‑5 and SH-SY5Y cells. In the respective primary tumours grown in SCID mice, the expression patterns of NCAM, polySia and polysialyl-transferases were similar to those observed in vitro. After subcutaneous engraftment, polySia-NCAM-positive neuroblastoma developed disseminated micrometastases, a metastatic pattern that was not observed for tumours derived from NCAM-negative cell lines. Together, this indicates that the presence of polySia reduces the adhesiveness of tumour cells and promotes dissemination.
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Polysialic acid
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Neural Development
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Purpose: Neural cell adhesion molecules (NCAM) and polysialic acid (polySia) are known to function in cell adhesion and cell migration processes. In neural development, polysialylated NCAM (polySia-NCAM) are closely associated with axon pathfinding, synaptogenesis, neural cell migration, differentiation, and myelination. The purpose of this explorative study was to determine if NCAM and polySia were expressed in spiral ganglion neuron and Schwann cells.
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Polysialic acid
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Neural Development
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Changes in carbohydrate and polypeptide form of the neural cell adhesion molecule (NCAM) have been documented during the development of central nervous system tissue in both chicken and frog. The carbohydrate variations reflect a high and low content of polysialic acid, and for the two vertebrates examined the expression of these forms is similar. At very early stages of neural development NCAM with a low content of polysialic acid is present, during histogenesis of the central nervous system NCAM with a high content of polysialic acid dominates, and there is a gradual return to NCAM with a low content of polysialic acid as the animals approach maturity. In contrast, the order of expression of the major NCAM polypeptide forms is different in the chicken and frog. These findings suggest that changes in sialic acid are a fundamental aspect of the function of NCAM in development, whereas NCAM polypeptide differences may affect events associated with a particular vertebrate. Studies have demonstrated that a decreased sialic acid content enhances the adhesion properties of NCAM. On this basis, we propose that NCAM with a low content of polysialic acid functions both to maintain integrity of neuroepithelium during morphogenesis of the early embryo and to stabilize differentiated structures in the adult, while the decreased adhesive function of NCAM with a high content of polysialic acid provides more plasticity in cell interactions during cell migration, axon outgrowth, and formation of neural circuits.
Polysialic acid
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N-Acetylneuraminic acid
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Polysialic acid (polySia) is a homopolymer of sialic acid with a degree of polymerization (DP) of 8–400. When present on neural cell adhesion molecule (NCAM), polySia has anti-adhesive effects on cell–cell interactions owing to its bulky polyanionic nature, and is involved in the regulation of neurogenesis and neuronal functions. Recently, we demonstrated that polySia functions not only as an anti-cell adhesion molecule, but also as a reservoir scaffold for brain-derived neurotrophic factor (BDNF) and fibroblast growth factor 2 (FGF2), which are biologically active molecules in neurogenesis. To understand the significance of polySia structure in the reservoir function, we focused on polySia-NCAM biosynthesized by mutated polysialyltransferase (ST8SiaII or STX) that was reported in a schizophrenia patient. The polySia-NCAM biosynthesized by mutant ST8SiaII/STX contained less polySia with shorter chain length and exhibited impaired reservoir function for BDNF and FGF2 as compared with that synthesized by wild-type (wt) ST8SiaII/STX. Our findings suggest that the quantity and quality of polySia on NCAM are important for normal neuronal functioning.
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Purpose: Neural cell adhesion molecules (NCAM) and polysialic acid (polySia) are known to function in cell adhesion and cell migration processes. In neural development, polysialylated NCAM (polySia-NCAM) are closely associated with axon pathfinding, synaptogenesis, neural cell migration, differentiation, and myelination. The purpose of this explorative study was to determine if NCAM and polySia were expressed in spiral ganglion neuron and Schwann cells.
Polysialic acid
Synaptogenesis
Neural cell
Neural Development
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Abstract By mediating cell adhesion and signal transduction, the neural cell adhesion molecule (NCAM) regulates neurite outgrowth, fasciculation and target recognition in the developing nervous system. In addition, a number of studies suggest an important role for the NCAM in regeneration and learning in the adult nervous system. NCAM‐deficient mice are impaired in spatial learning. Moreover, by interfering with normal NCAM function by intracranial injections of NCAM‐antibodies, long‐term potentiation (LTP) in rat hippocampal slices and learning in rats and chicks have been inhibited. In the vertebrate nervous system, NCAM is the dominant carrier of polysialic acid (PSA), an unusual carbohydrate consisting of long homopolymers of sialic acid. The PSA–NCAM expression decreases markedly during development. However, an upregulation of polysialic acid (PSA) in restricted brain areas including the hippocampus has been observed following learning. Moreover, enzymatic removal of PSA results in impaired LTP and learning. In muscle, the PSA–NCAM expression is upregulated following denervation. This response is weakened in aging rats. The expression of NCAM and PSA have been shown to be regulated by neuronal activity suggesting that the NCAM may promote structural remodelling in an activity dependent manner associated with learning and regeneration.
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