Proteoglycans in brain development and pathogenesis

Abstract

Edited by Sandro SonninoProteoglycans are diverse, complex extracellular/cell surface macromolecules composed of a central core protein with covalently linked glycosaminoglycan (GAG) chains; both of these components contribute to the growing list of important bio-active functions attributed to proteoglycans. Increasingly, attention has been paid to the roles of proteoglycans in nervous tissue development due to their highly regulated spatio/temporal expression patterns, whereby they promote/inhibit neurite outgrowth, participate in specification and maturation of various precursor cell types, and regulate cell behaviors like migration, axonal pathfinding, synaptogenesis and plasticity. These functions emanate from both the environments proteoglycans create around cells by retaining ions and water or serving as scaffolds for cell shaping or motility, and from dynamic interactions that modulate signaling fields for cytokines, growth factors and morphogens, which may bind to either the protein or GAG portions. Also, genetic abnormalities impacting proteoglycan synthesis during critical steps of brain development and response to environmental insults and injuries, as well as changes in microenvironment interactions leading to tumors in the central nervous system, all suggest roles for proteoglycans in behavioral and intellectual disorders and malignancies.Keywords: central nervous system; chondroitin sulfate; extracellular matrix; glycosaminoglycans; heparan sulfate; Proteoglycans; proteoglycaninteracting molecules Understanding the structure/function relationships, modes of interaction, spatial/temporal expression patterns, and functional roles of neural proteoglycans during brain development is essential for a full appreciation of the contributions of proteoglycans to establishment and maintenance of the nervous system. Increasingly, proteoglycans are implicated in developmental plasticity, recovery from injury, genetically induced defects that lead to intellectual disorders, and altered micro-environments that induce tumorigenesis. Lastly, promising new avenues of research exploration suggest proteoglycans may serve as biomarkers of disease and/or targets for therapy. Each of these areas is summarized in this review, highlighting how the modulation of proteoglycan structure promotes their ability to interact with diverse partners, thus regulating basic processes like proliferation and differentiation that in turn profoundly influence normal development which can lead to pathological conditions. Abbreviations ACAN,aggrecan; ADAMTS, disintegrin and metalloproteinases with thrombospondin motifs; BBB, blood-brain barrier; BCAN, brevican; BDNF, brain-derived neurotrophic factor; CHPF, chondroitin polymerazing factor; CHSY, chondroitin sulfate synthase; CNS, central nervous system;

The Role of Chondroitin Sulfate Proteoglycans in Nervous System Development

“…21,191 This increase in plasticity can alter ocular dominance, fear memory resilience, and enhance long-term recognition memory. 192 Components of PNNs include hyaluronic acid (HA), tenascin-R, link proteins, and CSPGs, including brevican, phosphacan, aggrecan, neurocan, and versican. 15,[21][22][23]34,41,45,48,54,193 HA binds to CSPGs through link proteins to help retain CSPGs and create the PNN.…”

Knockdown of chondroitin‐4‐sulfotransferase‐1, but not of dermatan‐4‐sulfotransferase‐1, accelerates regeneration of zebrafish after spinal cord injury

“…Chondroitin sulfate proteoglycans are a group of heterogeneous molecules that have been found to have a multitude of functions during nervous system development, in the adult and the traumatized nervous system of vertebrates (1)(2)(3)(4)(5)(6)(7)(8). Their functions range widely in various conditions that depend on the pattern of their sulfation as single epitopes and as different epitopes arranged in complex patterns on the glycan chain.…”

New Insights into ADAMTS Metalloproteases in the Central Nervous System

“…In the event of an injury, proteoglycan expression increases in the damaged area in order to promote the repair of the lesion. However, their expression has a dual role, since they are able to promote as well as inhibit neuronal growth depending on modifications of the ECM, which in turn serves to sustain cell formation, mobility, and growth factor and cytokine interactions [115]. Therefore, to maintain cellular homeostasis, this newly formed ECM, which is needed to support and sustain the repair process, has to be eliminated once it has fulfilled its scaffolding role in order to eliminate an environment that is nonpermissive of axonal regeneration in the glial scar.…”