研究者詳細 - 佐藤　ちひろ

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

Sato C, Kitajima K

Frontiers in cellular neuroscience 7 巻 ( APR ) 頁： 61 2013年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Frontiers in Cellular Neuroscience

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, 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 BDNF, FGF2, and dopamine 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. © 2013 Sato and Kitajima.

DOI： 10.3389/fncel.2013.00061

Sato, C

SIALOBIOLOGY: BIOSYNTHESIS, STRUCTURE AND FUNCTION: SIALIC ACID GLYCOCONJUGATES IN HEALTH AND DISEASE 頁： 33 - 75 2013年

ポリシアル酸による神経機能の調節. 実験医学 31巻 10号 (増刊) pp. 26-33; 第三の生命鎖査読有り

佐藤ちひろ

実験医学 31 巻頁： 26 - 33 2013年

Sialome analysis of the cephalochordate <i>Branchiostoma belcheri</i>, a key organism for vertebrate evolution Open Access

Guérardel, Y; Chang, LY; Fujita, A; Coddeville, B; Maes, E; Sato, C; Harduin-Lepers, A; Kubokawa, K; Kitajima, K

GLYCOBIOLOGY 22 巻 ( 4 ) 頁： 479 - 491 2012年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycobiology

Sialic acid, a common terminal substitution of glycoconjugates, has been so far consistently identified in all vertebrates as well as in a growing number of bacterial species. It is assumed to be widely distributed among animal species of the deuterostome phylum, based on its identification in few echinoderm and all vertebrate species. However, whole sections of deuterostome, especially those intermediate species between invertebrates and vertebrates including cephalochordates, urochordates and hemichordates, are still unexplored in term of sialylation capacities. The discovery of functional sialic acid machinery in some of these species may shed new light onto the evolution of glycosylation capacities in deuterostome lineage. In a first approach, we investigated the sialylation pattern of a cephalocordate species, Branchiostoma belcheri, which occupies a strategic phylogenetic position to understand the transition of invertebrates toward vertebrates. Structural analysis of B. belcheri glycoconjugates established that this organism synthesizes large quantities of various sialic acids, some of which present rare or novel structures such as methylated sialic acids. These sialic acids were shown to be mainly associated with mono-and disialylated core 1-type O-glycans. Moreover, screening of the animal organs revealed the existence of exquisite tissue specificity in the distribution of sialic acids. Description of sialylation profiles was then correlated with the expression patterns of key enzymes involved in the biosynthesis of major forms of sialic acids, which provides the first complete overview of the sialylation patterns in cephalochordates. © 2011 The Author.

DOI： 10.1093/glycob/cwr155

Structural and functional impairments of polysialic acid (polySia)-neural cell adhesion molecule (NCAM) synthesized by a mutated polysialyltransferase of a schizophrenic patient Open Access

Hane, M; Sumida, M; Kitajima, K; Sato, C

PURE AND APPLIED CHEMISTRY 84 巻 ( 9 ) 頁： 1895 - 1906 2012年

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Pure and Applied Chemistry

Polysialic acid (polySia) is a homopolymer of sialic acid with a degree of polymerization (DP) of 8-100. 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. © 2012 IU PAC.

DOI： 10.1351/PAC-CON-11-12-10

Co-expression of two distinct polysialic acids, α2,8- and α2,9-linked polymers of N-acetylneuraminic acid, in distinct glycoproteins and glycolipids in sea urchin sperm.

CiNii Research

Miyata S, Yamakawa N, Toriyama M, Sato C, Kitajima K

Glycobiology 21 巻 ( 12 ) 頁： 1596 - 605 2011年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycobiology

Naturally occurring polysialic acid (polySia) structures have a large diversity, primarily arising from the diversity in the sialic acid components as well as in the intersialyl linkages. In 2004, we demonstrated the presence of a new type of polySia, 8-O-sulfated N-acetylneuraminic acid (Neu5Ac) capped α2,9-linked polyNeu5Ac, on the O-glycans of a major 40-80 kDa sialoglycoprotein, flagellasialin, in sea urchin sperm. In this study, we demonstrated that another type of polySia, the α2,8-linked polyNeu5Ac, exclusively occurs on O-glycans of a 190 kDa glycoprotein (190 kDa-gp), whereas the α2,9-linked polyNeu5Ac is exclusively present on flagellasialin. The 190 kDa-gp is localized in both flagellum and head of sperm. We also demonstrated that polysialogangliosides containing the α2,8-linked polyNeu5Ac are present in sperm head. Thus, this study shows two novel features of the occurrence of polySia in nature, the co-localization of polySia with different intersialyl linkages, the α2,8-and α2,9-linkages, in a single cell and the occurrence of α2,8-linked polyNeu5Ac in glycolipids. Anti-α2,8-linked polyNeu5Ac antibody had no effect on fertilization, which contrasted with the previous results that anti-α2,9-linked polyNeu5Ac antibody inhibited sperm motility and fertilization. Based on these properties, distinct functions of α2,8-and α2,9-polySia structures are implicated in fertilization. © 2011 The Author.

DOI： 10.1093/glycob/cwr081

New Functions of Polysialic Acid and Its Relationship to Schizophrenia

Sato Chihiro, Kitajima Ken

TRENDS IN GLYCOSCIENCE AND GLYCOTECHNOLOGY 23 巻 ( 133 ) 頁： 221 - 238 2011年9月

記述言語：日本語掲載種別：研究論文（学術雑誌）出版者・発行元：Trends in Glycoscience and Glycotechnology

Polysialic acid (polySia), particularly α2,8-linked polyNeu5Ac (DP=8~400), is a unique polymer that spatiotemporally 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 antiadhesive 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 polySiadetection 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. ©2011 FCCA.

DOI： 10.4052/tigg.23.221

Structural and functional impairments of polysialic acid by a mutated polysialyltransferase found in schizophrenia. Open Access

CiNii Research

Isomura R, Kitajima K, Sato C

The Journal of biological chemistry 286 巻 ( 24 ) 頁： 21535 - 45 2011年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Journal of Biological Chemistry

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. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/jbc.M111.221143

IgG2 dominancy and carbohydrate recognition specificity of C3H/He mouse antibodies directed to cross-reactive carbohydrate determinants (CCDs) bearing beta-(1,2)-xylose and alpha-(1,3)-fucose.

Hino S, Umeda F, Inumaru S, Aoki N, Sato C, Okajima T, Nadano D, Matsuda T

Immunology letters 133 巻 ( 1 ) 頁： 28 - 34 2010年9月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Immunology Letters

Few common carbohydrate epitopes consisting of terminal β-(1,2)-xylose and/or α-(1,3)-fucose residues are shared by a variety of glycoproteins from plants, insects and parasitic worms, termed cross-reactive carbohydrate determinant (CCD), and frequently recognized by IgE antibodies of patients with food and/or respiratory allergy, though clinical relevancy of such CCD-specific IgE is still controversial. Attention has also been focused on CCDs from the undesired post-translational modification of recombinant therapeutic proteins produced by transgenic plants and insects. In the present study, to clarify immunogenic potentials of CCD-bearing glycoproteins, the antibody response to a model plant glycoprotein, horseradish peroxidase (HRP) was investigated in a mouse model. C3H/He mice were immunized with HRP plus Al(OH)3 or Freund's adjuvant, and IgG and IgE responses to CCDs in addition to HRP were analyzed by ELISA using some distinct glycoproteins with known N-glycan structures. IgE response to HRP was induced remarkably, whereas that to CCD was weaker and delayed. Moreover, apparent ratio of the CCD-specific antibodies to HRP-specific ones tended to be higher in IgG2a and IgG2b isotypes than IgG1, IgG3 and IgE. In contrast to rabbit antibodies, the CCD-specific antibodies from the mice gave poor reactivity with bromelain and honeybee phospholipase A2, suggesting the critical role of both β-(1,2)-xylose and α-(1,3)-mannose in the CCD-recognition by the mouse antibodies. Moreover, the mouse antibodies showed weaker cross-reactivity to pollen- and insect-derived glycoproteins than the rabbit ones. Thus, in this mouse model, not only IgE but also IgG2 antibody responses to CCDs were induced by immunizing with a CCD-bearing glycoprotein, suggesting that CCDs affected not only Th2-type but also Th1-type antibody response at least in C3H/He mice. © 2010 Elsevier B.V.

DOI： 10.1016/j.imlet.2010.06.007

Extensive enrichment of N-glycolylneuraminic acid in extracellular sialoglycoproteins abundantly synthesized and secreted by human cancer cells.

Inoue S, Sato C, Kitajima K

Glycobiology 20 巻 ( 6 ) 頁： 752 - 62 2010年6月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycobiology

N-Glycolylneuraminic acid (Neu5Gc) is the second most populous sialic acid (Sia). The only known biosynthetic pathway of Neu5Gc is the hydroxylation of cytidine-5′monophosphate-N-acetylneuraminic acid (CMP-Neu5Ac), catalyzed by CMP-Neu5Ac hydroxylase (CMAH). Neu5Gc is abundantly found in mammals except for human, in which CMAH is inactivated due to mutation in the CMAH gene. Evidence has accumulated to show occurrence of Neu5Gc-containing glycoconjugates in sera of cancer patients, human cancerous tissues and cultured human cell lines. Recently, occurrence of natural antibodies against Neu5Gc was shown in healthy humans and is a serious problem for clinical xenotransplantation and stem cell therapies. Studying human occurrence of Neu5Gc is of importance and interest in a broad area of medical sciences. In this study, using a fluorometric high performance liquid chromatography method, we performed quantitative analyses of Sias both inside and in the external environment of the cell and found that (i) incorporation of Neu5Gc was most prominent in soluble glycoproteins found both in the extracellular space and inside the cell as the major Sia compounds. (ii) Of the total Neu5Gc in the Sia compounds that the cells synthesized, 90% was found in the secreted sialoglycoproteins, whereas for Neu5Ac, 70% was found in the secreted sialoglycoproteins. (iii) The Neu5Gc ratio was higher in the secreted sialoglycoproteins (as high as 40% of total Sias) than in intracellular sialoglycoproteins. (iv) The majority of the secreted sialoglycoproteins was anchored on the culture dishes and solubilized by brief trypsin treatment. Based on these findings, a new idea on the mechanism of accumulation of Neu5Gc in cancer cells was proposed. © The Author 2010. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org.

DOI： 10.1093/glycob/cwq030

特集糖鎖のかかわる病気:発症機構,診断,治療に向けて糖鎖と統合失調症

佐藤ちひろ

生体の科学 61 巻 ( 2 ) 頁： 160 - 166 2010年4月

Measurement of glycan-based interactions by frontal affinity chromatography and surface plasmon resonance.

Sato C, Yamakawa N, Kitajima K

Methods in enzymology 478 巻 ( C ) 頁： 219 - 32 2010年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Methods in Enzymology

Proteins and lipids are often modified with glycan chains, which due to their large hydration effect and structural heterogeneity, significantly alter the surface physicochemical properties of proteins and biomembranes. This "glyco-atmosphere" also serves as a field for interactions with various molecules, including other glycans, lipids, peptides, proteins, and small molecules such as neurotransmitters and drugs as well as lectins. Therefore, sensitive techniques for measuring these glycan-based interactions are becoming more and more necessary, with the appropriate method largely depending on the interacting molecules. In this chapter, we focus on frontal affinity chromatography (FAC) and surface plasmon resonance (SPR) for examining polysialic acid-involved interactions with neurotransmitters and neurotrophins. FAC is characterized by its applicability to analyze weak interactions that are difficult to measure using conventional methods, and by the ease of principle and experimental procedures. SPR is advantageous due to the availability of suitable surface materials and for real-time monitoring with nonlabeled analytes. © 2010 Elsevier Inc.

DOI： 10.1016/S0076-6879(10)78010-1

Complex formation of a brain-derived neurotrophic factor and glycosaminoglycans.

糖鎖と統合失調症

佐藤ちひろ

生体の科学 61 頁： 160 - 166 2010年

Kanato Y, Ono S, Kitajima K, Sato C

Bioscience, biotechnology, and biochemistry 73 巻 ( 12 ) 頁： 2735 - 41 2009年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Bioscience, Biotechnology and Biochemistry

Glycosaminoglycans (GAGs), large anionic glycopolymers, are the glycan portion of proteoglycans and are important components of the extracellular matrix. Recently we reported that polysialic acid, a polyanionic glycopolymer specific to the brain, binds neurotrophic factors to form a large complex. It is not clear whether GAGs also bind neurotrophic factors to form a large complex. In the present study, we demonstrate that a brain-derived neurotrophic factor (BDNF) dimer directly binds GAGs other than chondroitin and hyaluronic acid to form a large complex. Neurotrophin-3 showed similar GAG binding properties. Furthermore, BDNF, after forming a large complex with GAG, bound to the BDNF receptors tropomyosin-related kinase (Trk) B and p75 neurotrophin receptor (NTR). These findings suggest that GAGs function to produce a reservoir of BDNF and other neurotrophic factors, and may serve to regulate their local concentrations on the cell surface.

DOI： 10.1271/bbb.90637

Developmental regulation of oligosialylation in zebrafish

Chang Lan-Yi, Harduin-Lepers Anne, Kitajima Ken, Sato Chihiro, Huang Chang-Jen, Khoo Kay-Hooi, Guerardel Yann

GLYCOCONJUGATE JOURNAL 26 巻 ( 3 ) 頁： 247 - 261 2009年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycoconjugate Journal

Zebrafish appears as a relevant model for the functional study of glycoconjugates along vertebrate's development. Indeed, as a prelude to such studies, we have previously identified a vast array of potentially stage-specific glycoconjugates, which structures are reminiscent of glycosylation pathways common to all vertebrates. In the present study, we have focused on the identification and regulation of major protein and lipids associated α2-8-linked oligosialic acids motifs in the early development of zebrafish. By a combination of partial hydrolysis, anion exchange HPLC-FD and mass spectrometry, we demonstrated that glycoproteins and glycolipids differed by the extent and the nature of their substituting oligosialylated sequences. Furthermore, relative quantifications showed that α2-8-linked sialylation was differentially regulated in both families of glycoconjugates along development. Accordingly, we established that α2,8-sialyltransferase mRNA levels was directly correlated with changes of α2,8-sialylation status of glycolipids, but independent of those observed on major glycoproteins that appear to originate from the mother. © 2008 Springer Science+Business Media, LLC.

DOI： 10.1007/s10719-008-9161-5

Membrane microdomains from early gastrula embryos of medaka, Oryzias latipes, are a platform of E-cadherin- and carbohydrate-mediated cell-cell interactions during epiboly.

Adachi T, Sato C, Kishi Y, Totani K, Murata T, Usui T, Kitajima K

Glycoconjugate journal 26 巻 ( 3 ) 頁： 285 - 99 2009年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycoconjugate Journal

Formation of membrane microdomain is critical for cell migration (epiboly) during gastrulation of medaka fish [Adachi et al. (Biochem. Biophys. Res. Commun. 358:848-853, 2007)]. In this study, we characterized membrane microdomain from gastrula embryos to understand its roles in epiboly. A cell adhesion molecule (E-cadherin), its associated protein (β-catenin), transducer proteins (PLCγ, cSrc), and a cytoskeleton protein (β-actin) were enriched in the membrane microdomain. LeX- containing glycolipids and glycoproteins (LeX-gp) were exclusively enriched in the membrane microdomain. Interestingly, the isolated membrane microdomain had the ability to bind to each other in the presence of Ca 2+. This membrane microdomain binding was achieved through the E-cadherin homophilic and the LeX-glycan-mediated interactions. E-cadherin and LeX-gp were co-localized on the same membrane microdomain, suggesting that these two interactions are operative at the same time. Thus, the membrane microdomain functions as a platform of the E-cadherin- and LeX-glycan-mediated cell adhesion and signal transduction. © 2008 Springer Science+Business Media, LLC.

DOI： 10.1007/s10719-008-9184-y

3P-066 シアル酸結合免疫グロブリン様レクチン(シグレック)-7によるシアロ糖鎖認識の生化学的および分子ドッキング解析(蛋白質-機能(反応機構,生物活性など),第47回日本生物物理学会年会)

生物物理 49 巻 ( supplement ) 頁： S162 2009年

Direct binding of polysialic acid to a brain-derived neurotrophic factor depends on the degree of polymerization.

Kanato Y, Kitajima K, Sato C

Glycobiology 18 巻 ( 12 ) 頁： 1044 - 53 2008年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Glycobiology

Polysialic acid (polySia) is the homopolymer of sialic acid and negatively regulates neuronal cell-cell and cell-extracellular matrix interactions through steric and repulsive hindrance due to its bulky polyanionic structure. Whether polySia also functions as a positive regulator in the nervous system through binding to specific ligands is not known. In the present study, we demonstrated that a brain-derived neurotrophic factor (BDNF) dimer binds directly to polySia to form a large complex with an Mr greater than 2000 kDa under physiologic conditions. Although somewhat affected by the linkage and type of sialic acid components in the polySia, the complex formation is highly dependent on the polySia chain length. The minimum degree of polymerization required for the complex formation is 12. This is the first study to demonstrate the biologic significance of the degree of polySia polymerization in eukaryotes. Similar large polySia complexes form with other neurotrophic factors such as nerve growth factor, neurotrophin-3, and neurotrophin-4. Furthermore, the BDNF, after making a complex with polySia, can bind to the BDNF receptors, TrkB and p75NTR. The complex formation of BDNF with polySia upregulates growth or/and survival of neuroblastoma cells. These findings suggest that polySia functions as a reservoir of BDNF and other neurotrophic factors and may serve to regulate their local concentrations on the cell surface. © The Author 2008. Published by Oxford University Press. All rights reserved.

DOI： 10.1093/glycob/cwn084