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Advanced Neurology HS-proteoglycans and brain function

However, due to their hydrophobic nature and poor recombinant tau, αsyn, and Aβ fibrils with HS have been
solubility, Wnt proteins require HSPGs for proper activity. determined using a small heparin mimetic library, which
HSPGs maintain solubility and facilitate the transport identified the critical size and sulfation positions required
of Wnt proteins, enabling the formation of gradients in for the formation of such protein aggregates. This
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tissues that drive developmental processes. Specifically, research has clarified the HS size and sulfation patterns
Wnt proteins bind to the low-density lipid receptor domain required to promote aggregate propagation. Specifically,
II of perlecan, which acts as a Wnt delivery vehicle during tau aggregates require a precise HS architecture containing
tissue development. N-, 6-O-, and 3-O-sulfated residues. In contrast, the
binding of α-syn and Aβ aggregates is less dependent on
2.1. The functional role of the HS glycocode and the these specific sulfation patterns. The internalization of tau
enigmatic 3-O HS sulfation motif protein and the propagation of its aggregates are regulated
HS GAG chains are typically depicted as linear structures, by 6-O-sulfation patterns on cell surface HSPGs, while 3-O
but they are actually helical assemblies with unique small sulfation of HS also enhances tau interaction and cellular
“kink(s)” where GlcA is epimerized to IdoA. The glycosidic uptake. Moreover, cell surface HSPGs play crucial roles
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linkages around IdoA offer greater chain flexibility, in the cellular attachment, subsequent internalization,
allowing for enhanced interaction of 3-O sulfation motifs fibril propagation, and spreading of both tau and α-syn
with a diverse range of ligands. Although 3-O sulfation fibrils. 21-24
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in HS is rare, it plays a crucial role in ligand interaction,
notably with antithrombin, Wnt, sonic hedgehog, SARS- 3. Lipid metabolism and amyloid
CoV2 spike protein, FGF receptor (FGFR), tau, and deposition in the Alzheimer’s disease (AD)
neuropilin-1. HS displays the most diverse “sulfation brain
codes” of any GAG, enabling selective recognition and
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interaction with numerous proteins, as reflected in HS The brain has the second-highest lipid content of all human
and GAG interactome databases. Specific HS sequences tissues, following adipose tissues, and lipids account for
have been identified that facilitate interactions with Wnt, 50% of the brain’s dry weight. Myelin, which functions
lipoprotein lipase, antithrombin, and FGF-FGFR. The as axonal insulation to ensure ultra-high conduction
sulfation of HS arises from the controlled spatiotemporal velocity of neural signaling, has significantly higher lipid
expression of a superfamily of N- or O-sulfotransferases. content (78 – 81% dry weight) compared to white matter
Seven isoforms of 3-O-sulfotransferases (HS3ST- (49 – 66%) or gray matter (36 – 40%). Accumulation of
1, -2, -3 , -3 , 4, -5, and -6) introduce 3-O-sulfation motifs different metals in brain tissues can lead to the production
A
B
into HS chains in the final biosynthetic step. Despite the of peroxides, reactive oxygen species, and free radicals,
relative scarcity of 3-O sulfation, its presence underscores resulting in lipid peroxidation and mitochondrial
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its importance as an interactive motif. Tau glycoprotein dysfunction, which can impair normal brain function.
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and SARS-CoV-2 spike glycoprotein have been shown to Minimizing lipid peroxidation through dietary flavonoids,
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preferentially bind to the 3-O-sulfation motif in HS. The which possess antioxidant and metal-chelating properties,
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sulfation sequences flanking the 3-O-sulfation motif also inhibit amyloid fibril assembly, and can be transported
contribute in an accessory capacity to the specificity of these through the gut-brain axis, holds promise as a therapeutic
interactive 3-O HS sequences, equipping HS with a diverse approach for neurodegenerative diseases. Apolipoprotein
dynamic recognition system through its 3-O-, 2-O-, and E2 (APOE2) gene therapy has been shown to reduce
6-O-sulfation motifs. This enables precise identification of amyloid deposition and neuroinflammation. The APOE
cell regulatory molecules and activation of growth factor isoformes—APOE2, APOE3, and APOE4—interact
receptors through a sulfation code, which is reflected in the with Aβ1-40, promoting its cellular retention. Notably,
co-receptor functions of cell surface HSPGs. 18 individuals carrying the ε4 APOE allele are at a greater risk
of developing AD and cerebral amyloid angiopathy, which
Tau is one of the few proteins that preferentially
bind to the 3-O-sulfated HS isoform. The formation of are associated with age-related cognitive decline.
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αsynuclein (α-syn) and βamyloid (Aβ) fibrils each requires 4. HS proteoglycans and diseases of
O-sulfation, as the removal of N-, 6-O-, or 2-O-sulfation cognitive decline
does not significantly inhibit this aggregative process,
highlighting the significant role of 3-O sulfation. The The brain contains a diverse array of proteoglycans
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binding of tau, Aβ, and αsyn to neuronal cell surface HSPGs (Table 1). HSPGs associated with pathological neural
promotes their cellular uptake and the seeding of protein tissues are implicated in the deposition of plaques and
aggregates in the brain. The GAG-binding requirements of fibrillary tangles involving tau protein, Aβ fibrils, and

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