Chondroitin sulphate and heparan sulphate proteoglycans (CSPGS and HSPGs) are found throughout the central nervous system (CNS). CSPGs are ubiquitous in the diffuse extracellular matrix (ECM) between cells and are a major component of perineuronal nets (PNNs), the condensed ECM present around some neurons. HSPGs are more associated with the surface of neurons and glia, with synapses and in the PNNs. Both CSPGs and HSPGs consist of a protein core to which are attached repeating disaccharide chains modified by sulphation at various positions. The sequence of sulphation gives the chains a unique structure and local charge density. These sulphation codes govern the binding properties and biological effects of the proteoglycans. CSPGs are sulphated along their length, the main forms being 6- and 4-sulphated. In general, the chondroitin 4-sulphates are inhibitory to cell attachment and migration, while chondroitin 6-sulphates are more permissive. HSPGs tend to be sulphated in isolated motifs with un-sulphated regions in between. The sulphation patterns of HS motifs and of CS glycan chains govern their binding to the PTPsigma receptor and binding of many effector molecules to the proteoglycans, such as growth factors, morphogens, and molecules involved in neurodegenerative disease. Sulphation patterns change as a result of injury, inflammation and ageing. For CSPGs, attention has focussed on PNNs and their role in the control of plasticity and memory, and on the soluble CSPGs upregulated in glial scar tissue that can inhibit axon regeneration. HSPGs have key roles in development, regulating cell migration and axon growth. In the adult CNS, they have been associated with tau aggregation and amyloid-beta processing, synaptogenesis, growth factor signalling and as a component of the stem cell niche. These functions of CSPGs and HSPGs are strongly influenced by the pattern of sulphation of the glycan chains, the sulphation code. This review focuses on these sulphation patterns and their effects on the function of the mature CNS.

Centre for Reconstructive Neuroscience Institute for Experimental Medicine Czech Academy of Science Prague Czechia

Department of Clinical Neurosciences John van Geest Centre for Brain Repair University of Cambridge Cambridge United Kingdom

Faculty of Biological Sciences School of Biomedical Sciences University of Leeds Leeds United Kingdom

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Akita K., von Holst A., Furukawa Y., Mikami T., Sugahara K., Faissner A. (2008). Expression of multiple chondroitin/dermatan sulfotransferases in the neurogenic regions of the embryonic and adult central nervous system implies that complex chondroitin sulfates have a role in neural stem cell maintenance. PubMed DOI

Allen N. J., Bennett M. L., Foo L. C., Wang G. X., Chakraborty C., Smith S. J., et al. (2012). Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. PubMed DOI PMC

Anderson M. A., O’Shea T. M., Burda J. E., Ao Y., Barlatey S. L., Bernstein A. M., et al. (2018). Required growth facilitators propel axon regeneration across complete spinal cord injury. PubMed DOI PMC

Brown J. M., Xia J., Zhuang B., Cho K. S., Rogers C. J., Gama C. I., et al. (2012). A sulfated carbohydrate epitope inhibits axon regeneration after injury. PubMed DOI PMC

Burnside E. R., De Winter F., Didangelos A., James N. D., Andreica E. C., Layard-Horsfall H., et al. (2018). Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury. PubMed DOI PMC

Carulli D., Kwok J. C., Pizzorusso T. (2016). Perineuronal Nets and CNS Plasticity and Repair. PubMed DOI PMC

Carulli D., Pizzorusso T., Kwok J. C., Putignano E., Poli A., Forostyak S., et al. (2010). Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. PubMed DOI

Chang A., Nishiyama A., Peterson J., Prineas J., Trapp B. D. (2000). NG2-Positive Oligodendrocyte Progenitor Cells in Adult Human Brain and Multiple Sclerosis Lesions. PubMed DOI PMC

Dayer A. G., Cleaver K. M., Abouantoun T., Cameron H. A. (2005). New GABAergic interneurons in the adult neocortex and striatum are generated from different precursors. PubMed DOI PMC

Deepa S. S., Carulli D., Galtrey C., Rhodes K., Fukuda J., Mikami T., et al. (2006). Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. PubMed DOI

Dick G., Tan C. L., Alves J. N., Ehlert E. M., Miller G. M., Hsieh-Wilson L. C., et al. (2013). Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains. PubMed DOI PMC

Dickendesher T. L., Baldwin K. T., Mironova Y. A., Koriyama Y., Raiker S. J., Askew K. L., et al. (2012). NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. PubMed DOI PMC

Ennemoser M., Pum A., Kungl A. (2022). Disease-specific glycosaminoglycan patterns in the extracellular matrix of human lung and brain. PubMed DOI

Esko J. D., Lindahl U. (2001). Molecular diversity of heparan sulfate. PubMed DOI PMC

Fawcett J. W., Asher R. A. (1999). The glial scar and CNS repair. PubMed DOI

Foscarin S., Raha-Chowdhury R., Fawcett J. W., Kwok J. C. F. (2017). Brain ageing changes proteoglycan sulfation, rendering perineuronal nets more inhibitory. PubMed DOI PMC

Garwood J., Schnädelbach O., Clement A., Schütte K., Bach A., Faissner A. (1999). DSD-1-proteoglycan is the mouse homolog of phosphacan and displays opposing effects on neurite outgrowth dependent on neuronal lineage. PubMed DOI PMC

Guglieri S., Hricovíni M., Raman R., Polito L., Torri G., Casu B., et al. (2008). Minimum FGF2 Binding Structural Requirements of Heparin and Heparan Sulfate Oligosaccharides As Determined by NMR Spectroscopy. PubMed DOI

Huynh M. B., Ouidja M. O., Chantepie S., Carpentier G., Maiza A., Zhang G., et al. (2019). Glycosaminoglycans from Alzheimer’s disease hippocampus have altered capacities to bind and regulate growth factors activities and to bind tau. PubMed DOI PMC

Ida M., Shuo T., Hirano K., Tokita Y., Nakanishi K., Matsui F., et al. (2006). Identification and Functions of Chondroitin Sulfate in the Milieu of Neural Stem Cells. PubMed DOI

Kalus I., Rohn S., Puvirajesinghe T. M., Guimond S. E., Eyckerman-Kolln P. J., Ten Dam G., et al. (2015). Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions. PubMed DOI PMC

Katagiri Y., Morgan A. A., Yu P., Bangayan N. J., Junka R., Geller H. M. (2018). Identification of novel binding sites for heparin in receptor protein-tyrosine phosphatase (RPTPsigma): implications for proteoglycan signaling. PubMed DOI PMC

Kempf A., Boda E., Kwok J. C. F., Fritz R., Grande V., Kaelin A. M., et al. (2017). Control of Cell Shape, Neurite Outgrowth, and Migration by a Nogo-A/HSPG Interaction. PubMed DOI

Kitagawa H., Ujikawa M., Tsutsumi K., Tamura J., Neumann K. W., Ogawa T., et al. (1997b). Characterization of serum beta-glucuronyltransferase involved in chondroitin sulfate biosynthesis. PubMed DOI

Kitagawa H., Tsutsumi K., Tone Y., Sugahara K. (1997a). Developmental regulation of the sulfation profile of chondroitin sulfate chains in the chicken embryo brain. PubMed DOI

Kondo T., Raff M. (2000). Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. PubMed DOI

Kowalewski B., Lange H., Galle S., Dierks T., Lübke T., Damme M. (2021). Decoding the consecutive lysosomal degradation of 3-O-sulfate containing heparan sulfate by Arylsulfatase G (ARSG). PubMed DOI

Kwok J. C., Warren P., Fawcett J. W. (2012). Chondroitin sulfate: a key molecule in the brain matrix. PubMed DOI

Lander C., Zhang H., Hockfield S. (1998). Neurons produce a neuronal cell surface-associated chondroitin sulfate proteoglycan. PubMed DOI PMC

Lang B. T., Cregg J. M., DePaul M. A., Tran A. P., Xu K., Dyck S. M., et al. (2015). Modulation of the proteoglycan receptor PTPsigma promotes recovery after spinal cord injury. PubMed DOI PMC

Lazaro-Pena M. I., Diaz-Balzac C. A., Bulow H. E., Emmons S. W. (2018). Synaptogenesis Is Modulated by Heparan Sulfate in Caenorhabditis elegans. PubMed DOI PMC

Levine J., Card J. (1987). Light and electron microscopic localization of a cell surface antigen (NG2) in the rat cerebellum: association with smooth protoplasmic astrocytes. PubMed DOI PMC

Lin R., Rosahl T. W., Whiting P. J., Fawcett J. W., Kwok J. C. (2011). 6-sulphated chondroitins have a positive influence on axonal regeneration. PubMed DOI PMC

Litjens T., Hopwood J. J. (2001). Mucopolysaccharidosis type VI: structural and clinical implications of mutations in N-acetylgalactosamine-4-sulfatase. PubMed DOI

Mah D., Zhao J., Liu X., Zhang F., Liu J., Wang L., et al. (2021). The Sulfation Code of Tauopathies: Heparan Sulfate Proteoglycans in the Prion Like Spread of Tau Pathology. PubMed DOI PMC

Maiza A., Sidahmed-Adrar N., Michel P. P., Carpentier G., Habert D., Dalle C., et al. (2020). 3-O-sulfated heparan sulfate interactors target synaptic adhesion molecules from neonatal mouse brain and inhibit neural activity and synaptogenesis in vitro. PubMed DOI PMC

Matthews R. T., Kelly G. M., Zerillo C. A., Gray G., Tiemeyer M., Hockfield S. (2002). Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. PubMed DOI PMC

McCanney G. A., McGrath M. A., Otto T. D., Burchmore R., Yates E. A., Bavington C. D., et al. (2019). Low sulfated heparins target multiple proteins for central nervous system repair. PubMed DOI PMC

Mikami T., Kitagawa H. (2013). Biosynthesis and function of chondroitin sulfate. PubMed DOI

Mikami T., Yasunaga D., Kitagawa H. (2009). Contactin-1 is a functional receptor for neuroregulatory chondroitin sulfate-E. PubMed DOI

Miller G. M., Hsieh-Wilson L. C. (2015). Sugar-dependent modulation of neuronal development, regeneration, and plasticity by chondroitin sulfate proteoglycans. PubMed DOI PMC

Miyata S., Komatsu Y., Yoshimura Y., Taya C., Kitagawa H. (2012). Persistent cortical plasticity by upregulation of chondroitin 6-sulfation. PubMed DOI

Morawski M., Bruckner G., Jager C., Seeger G., Arendt T. (2010). Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer’s disease. PubMed DOI

Morawski M., Filippov M., Tzinia A., Tsilibary E., Vargova L. (2014). ECM in brain aging and dementia. PubMed DOI

Nurcombe V., Ford M. D., Wildschut J. A., Bartlett P. F. (1993). Developmental regulation of neural response to FGF-1 and FGF-2 by heparan sulfate proteoglycan. PubMed DOI

Pearson C. S., Mencio C. P., Barber A. C., Martin K. R., Geller H. M. (2018). Identification of a critical sulfation in chondroitin that inhibits axonal regeneration. PubMed DOI PMC

Pearson C. S., Solano A. G., Tilve S. M., Mencio C. P., Martin K. R., Geller H. M. (2020). Spatiotemporal distribution of chondroitin sulfate proteoglycans after optic nerve injury in rodents. PubMed DOI PMC

Pizzorusso T., Medini P., Berardi N., Chierzi S., Fawcett J. W., Maffei L. (2002). Reactivation of ocular dominance plasticity in the adult visual cortex with chondroitinase ABC. PubMed DOI

Properzi F., Carulli D., Asher R. A., Muir E., Camargo L. M., van Kuppevelt T. H., et al. (2005). Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia. PubMed DOI

Properzi F., Lin R., Kwok J., Naidu M., van Kuppevelt T. H., ten Dam G. B., et al. (2008). Heparan sulphate proteoglycans in glia and in the normal and injured CNS: expression of sulphotransferases and changes in sulphation. PubMed DOI

Rauch J. N., Chen J. J., Sorum A. W., Miller G. M., Sharf T., See S. K., et al. (2018). Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). PubMed DOI PMC

Romberg C., Yang S., Melani R., Andrews M. R., Horner A. E., Spillantini M. G., et al. (2013). Depletion of Perineuronal Nets Enhances Recognition Memory and Long-Term Depression in the Perirhinal Cortex. PubMed DOI PMC

Rosenzweig E. S., Salegio E. A., Liang J. J., Weber J. L., Weinholtz C. A., Brock J. H., et al. (2019). Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury. PubMed DOI PMC

Rowlands D., Lensjo K. K., Dinh T., Yang S., Andrews M. R., Hafting T., et al. (2018). Aggrecan directs extracellular matrix mediated neuronal plasticity. PubMed DOI PMC

Ruzicka J., Dalecka M., Safrankova K., Peretti D., Mallucci G., Jendelova P., et al. (2021). Perineuronal nets affect memory and learning after synapse withdrawal. PubMed DOI PMC

Sahu S., Li R., Loers G., Schachner M. (2019). Knockdown of chondroitin-4-sulfotransferase-1, but not of dermatan-4-sulfotransferase-1, accelerates regeneration of zebrafish after spinal cord injury. PubMed DOI

Sakamoto K., Ozaki T., Ko Y. C., Tsai C. F., Gong Y., Morozumi M., et al. (2019). Glycan sulfation patterns define autophagy flux at axon tip via PTPRsigma-cortactin axis. PubMed DOI

Sarrazin S., Lamanna W. C., Esko J. D. (2011). Heparan sulfate proteoglycans. PubMed PMC

Sato Y., Nakanishi K., Tokita Y., Kakizawa H., Ida M., Maeda H., et al. (2008). A highly sulfated chondroitin sulfate preparation, CS-E, prevents excitatory amino acid-induced neuronal cell death. PubMed DOI

Schlessinger J., Plotnikov A. N., Ibrahimi O. A., Eliseenkova A. V., Yeh B. K., Yayon A., et al. (2000). Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. PubMed DOI

Schworer R., Zubkova O. V., Turnbull J. E., Tyler P. C. (2013). Synthesis of a targeted library of heparan sulfate hexa- to dodecasaccharides as inhibitors of beta-secretase: potential therapeutics for Alzheimer’s disease. PubMed DOI

Shida M., Mikami T., Tamura J. I., Kitagawa H. (2019). Chondroitin sulfate-D promotes neurite outgrowth by acting as an extracellular ligand for neuronal integrin alphaVbeta3. PubMed DOI

Sirko S., von Holst A., Weber A., Wizenmann A., Theocharidis U., Gotz M., et al. (2010). Chondroitin sulfates are required for fibroblast growth factor-2-dependent proliferation and maintenance in neural stem cells and for epidermal growth factor-dependent migration of their progeny. PubMed DOI

Sirko S., von Holst A., Wizenmann A., Götz M., Faissner A. (2007). Chondroitin sulfate glycosaminoglycans control proliferation, radial glia cell differentiation and neurogenesis in neural stem/progenitor cells. PubMed DOI

Sorg B. A., Berretta S., Blacktop J. M., Fawcett J. W., Kitagawa H., Kwok J. C., et al. (2016). Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity. PubMed DOI PMC

Steullet P., Cabungcal J. H., Coyle J., Didriksen M., Gill K., Grace A. A., et al. (2017). Oxidative stress-driven parvalbumin interneuron impairment as a common mechanism in models of schizophrenia. PubMed DOI PMC

Sugahara K., Kitagawa H. (2000). Recent advances in the study of the biosynthesis and functions of sulfated glycosaminoglycans. PubMed DOI

Sugahara K., Mikami T., Uyama T., Mizuguchi S., Nomura K., Kitagawa H. (2003). Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. PubMed DOI

Suttkus A., Holzer M., Morawski M., Arendt T. (2016). The neuronal extracellular matrix restricts distribution and internalization of aggregated Tau-protein. PubMed DOI

Suttkus A., Rohn S., Jager C., Arendt T., Morawski M. (2012). Neuroprotection against iron-induced cell death by perineuronal nets - an in vivo analysis of oxidative stress. PubMed PMC

Vegh M. J., Heldring C. M., Kamphuis W., Hijazi S., Timmerman A. J., Li K. W., et al. (2014). Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. PubMed DOI PMC

von Holst A., Sirko S., Faissner A. (2006). The unique 473HD-Chondroitinsulfate epitope is expressed by radial glia and involved in neural precursor cell proliferation. PubMed DOI PMC

Wang H., Katagiri Y., McCann T. E., Unsworth E., Goldsmith P., Yu Z. X., et al. (2008). Chondroitin-4-sulfation negatively regulates axonal guidance and growth. PubMed DOI PMC

Yamaguchi Y. (2001). Heparan sulfate proteoglycans in the nervous system: their diverse roles in neurogenesis, axon guidance, and synaptogenesis. PubMed DOI

Yang S., Cacquevel M., Saksida L. M., Bussey T. J., Schneider B. L., Aebischer P., et al. (2014). Perineuronal net digestion with chondroitinase restores memory in mice with tau pathology. PubMed DOI PMC

Yang S., Gigout S., Molinaro A., Naito-Matsui Y., Hilton S., Foscarin S., et al. (2021). Chondroitin 6-sulphate is required for neuroplasticity and memory in ageing. PubMed DOI PMC

Yang S., Hilton S., Alves J. N., Saksida L. M., Bussey T., Matthews R. T., et al. (2017). Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration. PubMed DOI

Yi J. H., Katagiri Y., Susarla B., Figge D., Symes A. J., Geller H. M. (2012). Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice. PubMed DOI PMC

Yoo M., Khaled M., Gibbs K. M., Kim J., Kowalewski B., Dierks T., et al. (2013). Arylsulfatase B improves locomotor function after mouse spinal cord injury. PubMed DOI PMC

Zhang X., Bhattacharyya S., Kusumo H., Goodlett C. R., Tobacman J. K., Guizzetti M. (2014). Arylsulfatase B modulates neurite outgrowth via astrocyte chondroitin-4-sulfate: dysregulation by ethanol. PubMed PMC

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