Central JSM Cell & Developmental Biology Review Article *Corresponding author Cintia Monteiro de Barros, Instituto de Biodiversidade e Sustentabilidade NUPEM/UFRJ Universidade Federal The Role of Dermatan Sulfate in do Rio de Janeiro, Av. São José do Barreto 764, São José do Barreto, 27910-970 Macaé, RJ, PO Box: 119331, Brazil, Fax: 55-21-22808193; Tel: 55-22-21413950; Email: the Nervous System [email protected] Submitted: 18 January 2021 Graziele Fonseca de Sousa1-3, Arthur Giraldi-Guimarães2, and Accepted: 01 April 2021 1 Cintia Monteiro de Barros * Published: 04 April 2021 1 Laboratório Integrado de Biociências Translacionais, Instituto de Biodiversidade e ISSN: 2379-061X Sustentabilidade, NUPEM/UFRJ, Universidade Federal do Rio de Janeiro, Brasil 2Laboratório de Biologia Celular e Tecidual , Centro de Biociências e Biotecnologia, Copyright Universidade Estadual do Norte Fluminense Darcy Ribeiro, Brasil © 2021 de Sousa GF, et al. 3Pós-Graduação em Biociências e Biotecnologia, Universidade Estadual do Norte OPEN ACCESS Fluminense Darcy Ribeiro, Brasil Keywords Abstract • Glycosaminoglycan • Neuritogenesis A lot of evidence suggests the crucial role of dermatan sulfate (DS), a glycosaminoglycan (GAG) present in the extracellular matrix (ECM) of the central nervous system (CNS), in brain • Extracellular matrix development, neuritogenesis, neuroprotection, and neuronal dysfunctions. Among these events, • Nuroprotection the involvement of DS during the development of the CNS has attracted attention to better comprehend its specific action in the neuroregeneration process. The various functions of DS can be mainly attributed to the structural variability of its disaccharides. Older and more recent reports about the relationship between the structure of DS and its function are helping to point out novel neurobiological roles for DS, increasing the understanding of a great range of biological functions of this molecule in the brain. Here we reviewed the recent knowledge about the function of DS, mainly in the neuritogenesis of the CNS. Furthermore, we indicate the importance of extending the in vitro and in vivo studies of the use of DS from marine organisms in the search for future therapeutic strategies. ABBREVIATIONS INTRODUCTION Akt: protein kinase B; AMPA: α-amino-3-hydroxy-5-methyl- The extracellular matrix (ECM) in the nervous system is 4-isoxazolepropionic acid; BBB: Blood Brain Barrier; BDNF: a complex meshwork of supporting molecules arranged in a Brain Derived Neurotrophic Factor; CNS: Central Nervous diffused way around the cell surface and/or associated with System; CS: Chondroitin Sulfate; CS-E: GalNAc(4,6-SO4) units; it. This ECM usually presents net-like formations surrounding neural cells. It is fundamental in maintaining the homeostasis of CSPG: Chondroitin Sulfate Proteoglycan; DS4ST1: DS-specific the CNS, acting as a scaffold for it and harboring chemical signaling 4-O-Sulfotransferase; GalNAc4S-6ST: N-acetylgalactosamine molecules that are important for several neural processes, both 4-sulfate 6-O-sulfotransferase; UST: Uronyl 2 Sulfotransferase; in physiological processes and in neural diseases [1-3]. ECM: Extracellular Matrix; FGF: Fibroblast Growth Factor; GAG: Glycosaminoglycan; GalNAc: N-acetyl-D-galactosamine; GAP-43: A lot of evidence suggests the involvement of dermatan Growth Associated Protein 43; HA: Hyaluronan; HA: Hyaluronan; sulfate (DS), a glycosaminoglycan (GAG) present in the ECM of the CNS, in brain development, neuritogenesis, and neuronal HCII: Heparin Cofactor II; HGF: Hepatocyte Growth Factor; dysfunctions. The main DS involved in neuritogenic activity is HP: Heparin; HS: Heparan Sulfate; iA: IdoUA-GalNAc (4S); iB: composed by oversulfated disaccharides that contain L-iduronic IdoUA (2S)-GalNAc (4S); iC: IdoUA-GalNAc(6S); iD: IdoUA(2S)- acid (IdoA) residues [4]. IdoA occurs in variable proportions in GalNAc(6S); IdoA: L-iduronic acid; iE: IdoUA-GalNAc(4S, 6S); iO: DS and, as a result of the different position of the carboxyl moiety IdoUA-GalNAc (iO); KS: Keratan Sulfate; MK: Midkine; mTOR: together with the different pattern of sulfation found in its Mammalian Target Rapamycin; NGF: Nerve Growth Factor; NgR: disaccharides, it generates a more flexible polysaccharide chain, Nogo Receptor; NMDA: N-MethylD-Aspartate; NSCs: Neurogenesis allowing specific interactions with several proteins and other of Neural Stem Cells; NSF: N-ethylmaleimide Sensitive Factor; polysaccharides. Thus, it has been suggested that DS has many PNNs: Perineuronal Nets; PSD95: Postsynaptic Density 95; PTN: potential neurobiological functions [5,6]. Pleiotrophin; RPTPs: Receptor Protein Tyrosine Phosphatases; DS is found relatively late in the evolutionary tree, first SEMA3s: Class III Semaphorins; SYN: Synaptophysin; UST: Uronyl appearing in the Echinodermata and Mollusca group of the animal 2-O-sulfotransferase; VEGF: Vascular Endothelial Growth Factor; kingdom [7]. It has been found in some invertebrate species and Wg: Wingless; Wnt-3a: Wingless/int-3a in the whole vertebrates group (subphylum Vertebrata) and it Cite this article: de Sousa GF, Giraldi-Guimarães A, de Barros CM (2021) The Role of Dermatan Sulfate in the Nervous System. JSM Cell Dev Biol 7(1): 1026. de Sousa GF, et al. (2021) Central is absent in the Nematoda, Platyhelminthes, Coelenterata, and C-5 to yield IdoA. Subsequently, O-sulfation may occur at the C-4 Porifera animal groups [8-11]. Moreover, DS has been found in [by dermatan 4-sulfate sulfotransferase 1 (D4ST1)] or C-6 [by large amounts in the tissues of some marine invertebrate species, N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (GalNAc4S- which represents a good source for its purification. 6ST) [25] and uronyl 2 sulfotransferase (UST) [26] positions of GalNAc or at the C-2 position of IdoA [reaction catalyzed by DS In this review, we will describe the role of DS in neuritogenesis, 2-O-sulfotransferase (DS2ST)]. Due to the epimerization and demonstrating the importance of this molecule in potential sulfation reactions the structure of DS is heterogeneous [27-29]. therapeuticGlycosaminoglycans strategies. The variety in the DS structure is responsible for providing these disaccharide subtypes: IdoUA-GalNAc (iO), IdoUA- GAGs are considered a fraction of the glycoconjugates in GalNAc(4S) (iA), IdoUA-GalNAc(6S) (iC), IdoUA (2S)-GalNAc(4S) the cell membranes, in the ECM, and in some cell granules of (iB), IdoUA(2S)-GalNAc(6S) (iD), and IdoUA-GalNAc(4S, 6S) (iE all tissues. The ability to connect protein to protein or enable or H) (Figure 1). These molecules include a range of molecular protein interactions is identified as an important determinant weights, from 12 to 45 kDa, with an average of around 25 kDa of the cellular response to development, homeostasis, and [30-32]. disease [13,14]. GAGs can act as a physical and biochemical The ratio of IdoUA to GlcUA varies depending on the tissue barrier, creating specific microenvironments around cells. They source or the animal species from which the molecule was build size-selective2+ barriers+ that are permeable only by small obtained [10,33,34,35,36], the stage of development [37-40], entities such as Ca and Na that can freely diffuse and promote as well as the purification method. The IdoUA content of DS extracellular cation homeostasis [15]. polymers may range from 1 to over 90%, even in many tissues GAGs are long, non-branched polysaccharides composed of from different animals and using different methodologies [41]. repeating disaccharide regions of uronic acid (D-glucuronic acid This sulfation pattern is responsible for a wide range or IdoA) and an amino sugar (D-galactosamine or D-glucosamine) of biological events involving DS, such as the assembly of or galactose [16]. They are distinguished from each other by the extracellular matrices, the transduction of signals through type of hexose, hexosamine, or hexuronic acid unit present and binding to growth factors, wound healing, and anticoagulation; by the geometry of the glycosidic linkage between the repeated and studies have demonstrated a stimulatory effect on neurite units [17]. outgrowth. Another important characteristic of the DS structure Based on the difference in the repeating disaccharide units is the IdoA content, which can vary depending of each organ, comprising GAGs, they can be categorized into six main groups: developmental stage, or animal species used to obtain the heparin (HP), heparan sulfate (HS), chondroitin sulfate (CS), molecule, among others [42-47]. dermatan sulfate (DS), keratan sulfate (KS), and hyaluronic acid For example, DS derived from porcine skin [48], marine (HA) [18]. clams [49], ascidians [50,51], the hagfish notochord [52], and Biosynthesis involves several enzymes that assemble the GAG backbone and subsequently add sulfate in their disaccharide at specific positions, except HA, which is a non-sulfated GAG [19]. Chains are synthesized by the attachment of a tetra- saccharide linker, which is covalently attached to the protein core. Following attachment of the linker to the protein core, the chain of glucosamine, galactosamine, or galactose is transferred, determining which type ofN GAG is produced [20,21]. Subsequently, the sugar chains are extended byN the addition of two alternating monosaccharides, either -acetylgalactosamine/glucuronic acid in chondroitin sulfate/DS or -acetylglucosamine/glucuronic acid in heparin/heparan sulfate, on the tetrasaccharide linker [22,23]. Figure 1 Typical repeating disaccharide units of DS, and