Page 49 - AN-3-3

Advanced Neurology HS-proteoglycans and brain function

for their production. There are around 20,000 specialized form of HS, lacks these less-modified regions
proteoglycan-associated genes listed in major human and is the most heavily modified GAG. HS biosynthesis
genome databases (GENCODE/Ensembl, RefSeq, and is not a template-driven process; rather, it is guided
UniProtKB). Approximately 50 proteoglycans, including by the activity of HS biosynthetic enzymes that are
1
18 heparan sulfate (HS) proteoglycans (HSPGs), have spatiotemporally expressed in tissues, contributing to the
11
been identified, and many excellent reviews have explored diversity of HS functional forms. HS is assembled from
their properties. These reviews highlight the diverse at least 12 different disaccharides, which are variably
2-5
roles of HSPGs in various biological processes, including distributed along an HS chain. The fine structure of HS
10
cell differentiation and proliferation, tissue development is remarkably diverse, theoretically allowing for an infinite
and morphogenesis, angiogenesis, skeletogenesis, and number of protein-binding epitopes, with over 1,000,000
extracellular matrix (ECM) remodeling during tissue structural epitopes possible in an HS octasaccharide. 12,13
repair. HSPGs also play critical roles in interactions with Cummings has calculated that for a typical interactive HS
12
growth factors and morphogens during tissue development, pentasaccharide, based on repeat disaccharides containing
matrix stabilization, and cell-matrix communication, all GlcA, IdoA, and IdoA2S at position 1, and GlcNAc, GlcNS,
of which are crucial for regulating tissue homeostasis. GlcNAc6S, GlcNS6S, GlcNS3S, and GlcNS3S6S at position
HS is an ancient glycocalyx molecule that evolved 2, there are 972 (3 × 6 × 3 × 6 × 3) possible structural
6
over a 500-million-year period as a highly diverse and combinations for one pentasaccharide and 1,944 (6 ×
essential cell regulatory molecule. Natural selection has 3 × 6 × 3 × 6) combinations for other, making a total of
7
favored HS for its versatility in molecular recognition, 2,916 possible pentasaccharide structural combinations.
information storage, and information transfer. The The spatiotemporal expression of defined HS structures
8
interactive properties of HSPG stem from the glycocode of and the modular core protein components of HSPGs are
9
their glycosaminoglycan (GAG) side chains and specific tightly regulated during embryonic development, skeletal
interactive modules within their core proteins, allowing maturation, and the specific features of pathological tissues.
them to interact with a wide range of cellular and structural
proteins (the HS interactome). The aim of this review is 2. HS sulfation as a key functional
to elucidate the role of HSPGs in the propagation and determinant of proteoglycans
deposition of pathological protein aggregates in the brain, A significantly higher 6O sulfation level in the HS chains
which contribute to the development of neurodegenerative of syndecan (SDC)-2 compared to those of SDC-4
processes and diseases associated with cognitive decline. correlates with increased reactivity of SDC-2 toward
1.1. HS biosynthesis vascular endothelial cell growth factor (VEGF)-2, leading
to enhanced activation and elevated neovascularization.
During the biosynthesis of HS, D-glucuronic acid (GlcA) This suggests that specific HS sulfation patterns
and N-acetylglucosamine (GlcNAc) are assembled in an contribute to the regulation of distinct biological activities
alternating fashion to form the repeating GlcA-GlcNAc in situ. Despite the importance of GAG multivalency in
14
disaccharide, which constitutes the backbone of HS. proteoglycan function, only a few studies have examined
10
The nascent HS chain undergoes further remodeling its biological significance. Two studies have proposed
through the actions of several families of modifying that dimerization or clustering of SDCs in focal adhesion
enzymes, adding complexity to the HS structure. One of complexes, along with the associated increase in charge
the initial steps in this process is the removal of the acetyl density, drives receptor activation and interactive processes
group from GlcNAc, followed by the addition of sulfate with fibroblast growth factor (FGF)2 and VEGF2. 15,16 This
groups. D-glucuronic acid can undergo epimerization to clustering increases FGF2-mediated cell signaling, cell
L-iduronic acid (IdoA), and its uronic acid groups can adhesion, and neovascularization. The diversity of GAG
be O-sulfated at the C2 position. Glucosamine can also side chain sequences attached to proteoglycan core proteins
be O-sulfated at the C6 position and less commonly at at the cell surface contributes to their cell-instructive and
the C3 position. The spatial and temporal regulation of ECM-interactive properties. These sequences modulate
10
glycosyltransferases and other HS-biosynthetic enzymes interactions with growth factors, chemokines, morphogens,
within tissues accounts for the diversity in HS structure proteases, and protease inhibitory proteins, acting as cell-
observed during tissue development and in pathological responsive cues delivered by the ECM. The Wnt signaling
11
conditions. Sulfation along the HS chain is not uniform; pathway plays an important role in regulating embryonic
HS chains contain regions of high sulfation interspersed tissue development and adult tissue homeostasis. Wnt
with domains of high acetylation, non-sulfated regions, proteins, which are secreted lipid-modified glycoproteins,
and less-modified de-acetylated regions. Heparin, a form morphogen gradients that direct cellular behavior.

Volume 3 Issue 3 (2024) 2 doi: 10.36922/an.3812