Proteoglycan Sulphation in the Function of the Mature Central Nervous System

Abstract

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.

Perineuronal nets affect memory and learning after synapse withdrawal

“…In CA2 LTP and excitability were increased by digestion of PNNs, which in this region surround pyramidal cells [ 57 , 58 ]. PNN removal affects memory and plasticity largely through effects on PV + interneurons, which affect network activity through modulation of GABA-mediated plasticity [ 45 , 47 , 59 ].…”

HS, an Ancient Molecular Recognition and Information Storage Glycosaminoglycan, Equips HS-Proteoglycans with Diverse Matrix and Cell-Interactive Properties Operative in Tissue Development and Tissue Function in Health and Disease

“…Thus 3- O , 2- O and 6- O sulfation motifs in HS equip it with a diverse dynamic recognition system for the precise identification of bioactive cell regulatory molecules through a “sulfation code” [ 100 , 101 ]. This is reflected in the co-receptor functions of cell surface HS-PGs [ 68 ] and the diverse roles of HS-PGs in the stabilization and functional properties of ocular tissues [ 102 ], and neural activity in the CNS/PNS [ 103 ]. HS-PG interactions with neural cell surface cell attachment glycoproteins provide synaptic stabilization [ 104 , 105 , 106 ] and the signalling properties of neural networks [ 106 ].…”

“…While HS-PGs are associated with PNNs, they are not however considered to be integral functional components of the PNN scaffold which is composed primarily of CS-PGs. The sulfation patterns of the PNN CS-PGs are however recognized to have important cell instructional roles, a feature shared by HS-PGs [ 103 , 351 ]. Neurons in the PNNs also synthesise cell surface HS-PGs through which instructive ECM cues to cells may be enacted upon.…”

“…Dysfunctional neurexin activity has been identified in a range of psychiatric disorders including schizophrenia, autism, intellectual disability, and addictive disorders [ 357 ]. The variable HS sulfation patterns of neurexins contributes to their diverse interactive features in the synapse with a wide range of ligands in health and disease [ 103 , 358 ]. The synapse contains a very diverse range of HS interactive ligands that are important for neural activity and message transduction in neural networks [ 106 , 344 ].…”

“…Neuronal RPTP-σ acts as a PG receptor binding HS-PGs and CS-PGs and these convey cell instructive signals. CS-PGs generally transmit inhibitory signals that down regulate proliferation and neural outgrowth from gliotic scars impeding functional repair of brain tissues from traumatic injury whereas HS-PGs convey signals that promote neural proliferation, migration, and neural outgrowth [ 49 , 103 ]. The collective interplay of HS-PGs and CS-PGs thus regulates tissue development, homeostasis, tissue remodelling and repair processes in health and disease [ 366 , 373 , 374 ].…”