The DSD-1 Carbohydrate Epitope Depends on Sulfation, Correlates with Chondroitin Sulfate D Motifs, and Is Sufficient to Promote Neurite Outgrowth

Clement, Albrecht M.; Nadanaka, Satomi; Masayama, Kimiko; Mandl, Claudia; Sugahara, Kazuyuki; Faissner, Andréas

doi:10.1074/jbc.273.43.28444

Cited by 177 publications

(151 citation statements)

References 76 publications

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“…Nevertheless, the repartition of negative charges in space that has been characterized here is likely to be determinant for the antibody during the recognition process. The CS-56 epitope is strongly expressed in the postnatal mouse brain cerebral cortex, whereas the MO-225 epitope is found in other regions of mouse developing brain (16), and the 473HD epitope is highly present in the cerebellum of adult mouse (12).…”

Section: H Nmr Spectroscopy Of ∆C-a-d-cmentioning

confidence: 99%

“…The CS-PG named DSD-1-PG, located on the surface of immature glial cells in the CNS in developing mouse brain, promotes neurite outgrowth (11). The disulfated disaccharide D [GlcA2S( 1-3)GalNAc6S] (Figure 1), being the major component in shark cartilage CS-D, is also present in some neurotrophic CS-PGs such as DSD-1-PG (12). Monoclonal antibody (mAb) 473HD, which recognizes an epitope of DSD-1-PG, strongly reduces neurite outgrowth stimulation.…”

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confidence: 99%

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Conformational Studies on Five Octasaccharides Isolated from Chondroitin Sulfate Using NMR Spectroscopy and Molecular Modeling

et al. 2007

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Chondroitin sulfate proteoglycans (CS-PG) are involved in the regulation of the central nervous system in vertebrates due to their presence on cell surfaces and in the extracellular matrix of tissues. The CS moieties are built up from repeating -4)GlcA( 1-3)GalNAc( 1-disaccharide units, partly O-sulfated at different positions. The presence of the disulfated disaccharide D-unit, GlcA2S( 1-3)GalNAc6S, in the CS moiety of the proteoglycan DSD-1-PG/phosphacan, correlates with neurite outgrowth promotion. The binding of monoclonal antibody (mAb) 473HD to DSD-1-PG, reducing neuronal stimulation, is inhibited by shark cartilage CS-D. CS-D is also recognized by two other mAbs, MO-225 and CS-56. Conformational studies were performed using NMR spectroscopy and molecular modeling on five octasaccharides isolated from shark cartilage CS-D. These octasaccharides present different binding properties toward the three mAbs. The combination of the experimental and theoretical approaches revealed that the sulfate group at position 2 of GlcA in disaccharide D and the presence of an exocyclic negative tail in disaccharides C [GlcA( 1-3)GalNAc6S] and ∆C [∆ 4,5 HexA(R1-3)GalNAc6S] are important for antibody recognition.

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Section: H Nmr Spectroscopy Of ∆C-a-d-cmentioning

confidence: 99%

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confidence: 99%

Conformational Studies on Five Octasaccharides Isolated from Chondroitin Sulfate Using NMR Spectroscopy and Molecular Modeling

et al. 2007

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“…To generate a CS-E blocking agent, we raised a monoclonal antibody against a pure synthetic CS-E tetrasaccharide (28). Although antibodies have been generated previously using CS polysaccharides as antigens (29,30), their specificity has been limited by the structural heterogeneity of natural polysaccharides. Synthetic chemistry has the advantage of providing defined molecules of precise sulfation sequence, which can be used as antigens, for screening antibodies, and for characterizing binding specificities.…”

Section: Pure Cs-e Potently Inhibits Neurite Outgrowth and Collapses mentioning

confidence: 99%

A sulfated carbohydrate epitope inhibits axon regeneration after injury

Brown

Xia

Zhuang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Chondroitin sulfate proteoglycans (CSPGs) represent a major barrier to regenerating axons in the central nervous system (CNS), but the structural diversity of their polysaccharides has hampered efforts to dissect the structure-activity relationships underlying their physiological activity. By taking advantage of our ability to chemically synthesize specific oligosaccharides, we demonstrate that a sugar epitope on CSPGs, chondroitin sulfate-E (CS-E), potently inhibits axon growth. Removal of the CS-E motif significantly attenuates the inhibitory activity of CSPGs on axon growth. Furthermore, CS-E functions as a protein recognition element to engage receptors including the transmembrane protein tyrosine phosphatase PTPσ, thereby triggering downstream pathways that inhibit axon growth. Finally, masking the CS-E motif using a CS-Especific antibody reversed the inhibitory activity of CSPGs and stimulated axon regeneration in vivo. These results demonstrate that a specific sugar epitope within chondroitin sulfate polysaccharides can direct important physiological processes and provide new therapeutic strategies to regenerate axons after CNS injury.

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“…NOP activity toward hippocampal cells from E16 mice was assayed as described [9,13]. Briefly, 2 µg/well of the CS preparation was coated onto coverslips precoated with P-ORN at 4 ˚C overnight.…”

Section: Assays For Nop Activitymentioning

confidence: 99%

“…Several studies have shown that the sulfation pattern of CS in the brain alters during development, characterized by an increase in 4-O-sulfation and a decrease in 6-O-sulfation [5,6]. The proportion of oversulfated disaccharide units, GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate) and GlcUA-GalNAc(4,6-O-disulfate), has been demonstrated to be crucial to the neurite outgrowth-promoting (NOP) activity of CS [7][8][9][10][11][12][13]. The NOP activity toward embryonic mouse hippocampal neurons of mouse brain CS/DS and shark cartilage CS/DS, which contains a high proportion of the GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate) unit [13], has been verified to be executed by capturing endogenous growth/neurotrophic factors produced by non-neuronal cells (glial cells), and then presenting them to neuronal cells [4,14,15].…”

Section: Introductionmentioning

confidence: 99%

Demonstration of the hepatocyte growth factor signaling pathway in the in vitro neuritogenic activity of chondroitin sulfate from ray fish cartilage

Hashiguchi

Kobayashi

Fongmoon

et al. 2011

Biochimica et Biophysica Acta (BBA) - General Subjects

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Chondroitin sulfate (CS) was isolated from ray fish cartilage, an industrial waste, after protease digestion, and its structure and neurite outgrowth-promoting (NOP) activity were analyzed to investigate a potential application to nerve regeneration.A disaccharide analysis using chondroitinase ABC revealed that the major unit in the CS preparation was GlcUA-GalNAc(6-O-sulfate) (63%), where GlcUA and GalNAc represent D-glucuronic acid and N-acetyl-D-galactosamine, respectively. Small proportions of other disaccharide units, GlcUA-GalNAc(4-O-sulfate) (25%), GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate) (7%), and GlcUA-GalNAc (5%), were also detected. The average molecular mass of CS was estimated to be 142 kDa by gel-filtration chromatography. The prepration showed NOP activity in vitro, which was eliminated by digestion with chondroitinase ABC, suggesting that a polymeric structure is required for the activity. Antibodies against hepatocyte growth factor (HGF) and its receptor c-Met suppressed the NOP activity, suggesting the involvement of the HGF signaling pathway in the in vitro NOP activity of the CS preparation. Since the specific binding of HGF to the CS preparation was also demonstrated by surface plasmon 3 resonance spectroscopy, the CS chains were fractionated using an HGF-immobilized column into unbound and bound fractions accounting for 44 and 56% of the total yield,

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The DSD-1 Carbohydrate Epitope Depends on Sulfation, Correlates with Chondroitin Sulfate D Motifs, and Is Sufficient to Promote Neurite Outgrowth

Abstract: The neural chondroitin sulfate (CS) proteoglycan (PG)DSD

Cited by 177 publications

References 76 publications

Conformational Studies on Five Octasaccharides Isolated from Chondroitin Sulfate Using NMR Spectroscopy and Molecular Modeling

Conformational Studies on Five Octasaccharides Isolated from Chondroitin Sulfate Using NMR Spectroscopy and Molecular Modeling

A sulfated carbohydrate epitope inhibits axon regeneration after injury

Demonstration of the hepatocyte growth factor signaling pathway in the in vitro neuritogenic activity of chondroitin sulfate from ray fish cartilage

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