TABLE 1.
Extracellular, cell associated and intracellular CS-proteoglycans of the CNS/PNS.
| Protein | Distribution | Roles | References |
| Large lectican neural proteoglycans | |||
| Aggrecan (ACAN) (CSPG1) | Present as diffuse ECM component between the dense ECM of PNNs which contain HA and the lecticans | Roles in tissue hydration, space-filling in CNS/PNS, neuroprotective in PNNs, synapse formation, roles in synaptic plasticity memory, cognitive learning | Kiani et al., 2002; Hayes and Melrose, 2020a |
| Versican (VCAN) (CSPG2) | Widespread in CNS/PNS occurs as V0, V1, V2, V3 isoforms | Promotes proliferation, differentiation, cell migration, tissue development, repair, tissue morphogenesis. G1 and G3 stimulate cell migration. Versikine G1 fragment of Versican V2 is an Alarmin in innate immunity with TLR4. | Schmalfeldt et al., 1998; Wu et al., 2004; Xiang et al., 2006; Schmitt, 2016; Islam and Watanabe, 2020 |
| Neurocan (NCAM) (CSPG3) | 150 kDa lectican CS-PG Widespread CNS/PNS PG | Interacts with HA, NCAM, modulates cell binding, regulates neurite outgrowth through interactions with Sdc-1, Gpc-3, and PTN. | Margolis and Margolis, 1994; Margolis et al., 1996; Rauch et al., 2001; Sullivan et al., 2018; Schmidt et al., 2020 |
| Brevican (CSPG7) | Widespread CNS/PNS PG, present in the post synaptic gap where it may relay neurotransmitters to adjacent communicating neurons | Binds to astrocytes and neurons regulates axon and dendritic maturation, upregulated in glial scars. GPI anchored brevican described. BEHAB is a bioactive fragment that promotes glioblastoma development. | Yamaguchi, 1996; Gary and Hockfield, 2000; Matthews et al., 2000; Giamanco and Matthews, 2020 |
| Large non-lectican neural proteoglycans | |||
| RPTPR-ζ Phosphacan | Populations of phosphacan contain variable levels of CS, KS, or HNK-1 trisaccharide substitution Cell surface (RPTPR-ζ) and soluble PG (phosphacan) forms | RPTPR-ζ, single pass type 1 TM PG-phosphatase receptor, regulates SC repair and neurogenesis, soluble phosphacan ectodomain, has truncated forms with neurite outgrowth activity. | Garwood et al., 2003; Faissner et al., 2006; Eill et al., 2020 |
| NG2 (CSPG4) | Widely distributed TM Oligodendrocyte PG, a soluble form is released from cell by proteases | Stimulates endothelial cell proliferation, sequesters FGF-2 and PDGF. Collagen VI receptor activates FAK/ERK1/ERK2 signaling. Up-regulated in SCI and tumors. | Jones et al., 2002; Wigley et al., 2007; Tamburini et al., 2019 |
| Betaglycan | 250–280 kDa CS/HS TM homodimeric PG | Binds inhibin, FGF-2, Wnt TGF-β HS inhibits and CS promotes Wnt signaling. Fragments of betaglycan are released by plasmin and MMPs. binding to inhibin antagonises activin signaling | Lewis et al., 2000; Gray et al., 2001; Bilandzic and Stenvers, 2011; Miller et al., 2012; Kim et al., 2019 |
| Perlecan (HSPG2) | HS/CS hybrid PG of BBB, NMJ, BM, and of fractone stem cell niche | Stabilizes BBB and motor neuron endplate BM. Regulates neuroprogenitor proliferation by FGF-2 in SVZ and dentate gyrus fractones. Domain V promotes neurogenesis, BBB repair | Cho et al., 2012; Kerever et al., 2014; Celestrin et al., 2018 |
| Small neural proteoglycans | |||
| Neuroglycan-C (CSPG5, CALEB) Acidic, Leu-rich EGF Brain PG | Part-time TM PG, growth and differentiation factor involved in neuritogenesis | Core protein EGF domain, CS-E side chains, ligand for ErbB3. Binds PTN to promote neurite outgrowth. | Watanabe et al., 1995; Kinugasa et al., 2004; Shuo et al., 2007; Nakanishi et al., 2010 |
| Syndecan-1. Syndecan-3 (Sdc1, Sdc3) | TM CS/HS CNS/PNS PGs | Sdc-1 and 3 interact with midkine, and PTN, roles in neural development, neurite outgrowth, neural proliferation | Couchman et al., 2015; Gopal et al., 2016 |
| Decorin (DCN) | ∼92.5 kDa class I SLRP containing one N-terminal CS or DS chain, 42 kDa core protein, and 12 LRRs. Widely distributed in CNS/PNS and around gliotic scars | Pluripotent, regulates IL-1, VEGF2, CTGF, TGF-β EGF, IGF-1, participates in ECM assembly, cell growth, differentiation, proliferation, adhesion, and migration. Regulates inflammation, fibrosis, fibrillogenesis, TGF-β bioavailability. “Mayday” and “Decorunt” DCN fragments. Mayday attracts MSCs into tissue defects | Lee et al., 2014; Zhang W. et al., 2018 |
| Biglycan (BGN) | ∼200 kDa class I SLRP containing two N-terminal CS or DS chains and a 42 kDa core protein and 12 LRRs | Structural ECM component, TLR-2, 4 interactive DAMP Alarmin protein in innate immunity, modulates growth factor (TGF-β, TNFα, BMP-2, 4, 6; WISP-1) and cytokine functions and is a stabilizing component of synapses. also interacts with complement system. An en silico generated BGN fragment (P2K) is a TGF-β inhibitor. | Amenta et al., 2012; Nastase et al., 2012; Chen et al., 2018, 2020; Xie et al., 2020 |
| Epiphycan (EPN) DSPG3,PG-Lb | Epiphycan (EPN) also known as DSPG3 or PG-Lb is a CS/DS substituted 133 kDa SLRP with a 46 kDa core protein and contains 7 LRR repeats. EPN is a Cochlear SLRP | Epiphycan (EPN) is a CS/DS 133 kDa SLRP with a 46 kDa core protein and c7 LRR repeats. EPN has roles in auditory cochlear neuronal interactions, EPN deficiency leads to deafness. | Johnson et al., 1997; Hanada et al., 2017 |
| Appican (APP) | APP is a 100–110 kDa type I TM PG alternatively spliced APLP2 is also found in neural tissues | APP has neuroregulatory properties through PTN: CS-E interactions | Pangalos et al., 1996 |
| Bikunin/ITI | Bikunin is the light chain of ITI and has a mass of 25–26 kDa, contains a single CS chain. | Multifunctional Kunitz protease inhibitor PG, anti-metastatic, immune-modulator, growth promoter. Stabilizes HA by crosslinking ITI HCs to HA | Hamasuna et al., 2001; Lord et al., 2013, 2020 |
| Serglycin (SGN) | Mast cells, platelets, macrophages, T-cell, NK cells | Mast cell SGN is substituted with heparin, macrophage, NK killer, T-cell SGN has CS (CS-A, CS-E) side chains | Kolset and Pejler, 2011; Roy et al., 2017 |
| Endocan | 50 kDa Endothelial cell DS cell surface PG also found circulating in bloodstream | DS chain binds L-, P-Selectin FN, chemokines, cytokines. RANTES, SDF-1β, IL-8, MCP-1, IFN-γ, PF-4, MK, PTN, FGF-2, FGF -7 | Maurage et al., 2009; Kali and Shetty, 2014; Gaudet et al., 2020 |
| Testican-1, 2, 3 | Testican-1 and -2 are CS/HS PGs, of the BM-40/SPARC/osteonectin family. Testican 3 is a brain specific HS PG | Testican-1 is upregulated in neurons and astrocytes following brain injury. Testican 1-3 regulate MT_MMP and cathepsin L activity in neural tissues. | Marr et al., 2000; Iseki et al., 2011; Hartmann et al., 2013 |
| CD 141 | Thrombomodulin is a component of the endothelium, thrombin inhibitor | Inhibits thrombin in the endothelium protein C- anticoagulant system. Has anti-inflammatory barrier-stabilizing properties in ischemic stroke, enhancing vessel recovery and BBB repair. | |
| CD44 | V3 splice variants bear CS chains | Binds Ezrin, fibrin/fibrinogen, FN, HA, OPN, Selectins-P,-E,-L. | Dzwonek and Wilczynski, 2015; Mooney et al., 2016 |
| CD47 | Neuron 50 KDa, 4 span TM CS-PG receptor | Neuroimmune regulatory protein, TSP-1 receptor, binds SIRPα. Regulates neuronal migration, proliferation and vascular cell survival, in innate and adaptive immunity, increases tissue resilience | Zhang H. et al., 2015; Matlung et al., 2017; Bedoui et al., 2018; Hutter et al., 2019; Li et al., 2021 |
| Astrochondrin | Astrocyte cell surface PG | Binds laminin and type IV collagen in microvasculature and meninges. | Streit et al., 1993 |
| Photomedin | Brain-specific glycoprotein of the eye neuroepithelium. member of the olfactomedin protein family | Photomedin interacts with CS-E to regulate axonal growth and differentiation of neural sensory epithelium | Furutani et al., 2005 |
| FORSE-1 PG (forebrain-surface-embryonic) | LeX-substituted 286 kDa neuro-progenitor cell glycoprotein/PG | Lewis-X, SSEA-1 or CD15, Galβ(1-4)Fucα(1-3)GlcNAc-R oligosaccharide epitopes in FORSE-1 have roles in embryonic neural development | Gooi et al., 1981; Hakomori et al., 1981; Allendoerfer et al., 1995, 1999; Kelly et al., 2019 |
ADAM-TS, a disintegrin and metalloproteinase with thrombospondin motifs; BBB, blood brain barrier; BM, basement membrane; BMP, bone morphogenic protein; CNS, central nervous system; CS, chondroitin sulfate; DS, dermatan sulfate; ECM, extracellular matrix; ERK, extracellular regulated kinase; FAK, focal adhesion kinase; FGF-2, fibroblast growth factor-2; HA, hyaluronic acid; HS, heparan sulfate; IL1, interleukin-1; LRR, leucine rich repeat; MMP, matrix metalloproteinase; MS, mass spectrometry; NCAM, neural cell adhesion molecule; PCM, pericellular matrix; PNS, peripheral nervous system; SLRP, small leucine repeat proteoglycan; SV, sub-ventricular; TLR4, Toll-like receptor-4; TM, transmembrane; TNF-α, tumor necrosis factor-α; MK, midkine; PTN, pleiotrophin; FN, fibronectin; TSP, thrombospondin; SGN, serglycin; ITI, inter-α-trypsin inhibitor; SVZ, sub-ventricular zone; WISP-1, Wnt1-inducible-signaling pathway protein 1, CCN4; SDF-1, stromal cell derived factor-1, CXCL12; MCP-1, monocyte chemoattractant protein-1, CCL2; RANTES, Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted, chemokine ligand 5 (CCL5); PF-4, platelet factor-4; SSEA-1, stage specific embryonic antigen-1; DAMP, danger associated molecular pattern; SPARC, secreted protein acidic and rich in cysteine.