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Advanced Neurology HS-proteoglycans and brain function

as useful tools for better understanding HS interactions of HS-ligand recognition and interaction. In addition,
physiological significance. Another novel approach in HS artificial intelligence, deep machine learning, and neural
glycomimetics involves the use of clickable disaccharide network analysis have been applied in the development
building blocks to assemble oligomers that mimic the of interactive algorithms for understanding HS structure
disaccharide repeat units of native HS. These HS-mimetic and function, and these technologies are being used in the
91
oligomers also bind FGF-2 in a sulfation-dependent manner. development of HS mimetics with potential therapeutic
To further explore HS structure-function relationships and applications. A greater understanding of HS-protein
harness the therapeutic potential of HS, a new class of four interactions through these sophisticated techniques
trisaccharide compounds derived from the aminoglycoside will undoubtedly further our understanding of the
95
tobramycin has been identified. These compounds mimic complexities of this fascinating molecule. However,
natural HS, exhibiting strong binding to heparanase finding a means to control HS in pathological disorders
92
while displaying low affinity to off-target platelet factor-4, without disrupting its roles in essential life processes will
thereby demonstrating their potential as glycopolymers be a challenging task. If successful, it could have profound
96
with specific modes of action. Some functions of HS benefits for health and well-being. Achieving this goal
chains, such as receptor activation, require short sulfated will require the utilization of next-generation, state-of-
sequences separated by N-acetylated regions. Advances in the-art technologies, but promising bioactive molecules
HS sequencing, chemical synthesis, and the elucidation have already emerged. Ongoing work will hopefully
of 3D oligosaccharide-protein complex structures have continue to refine these developments, perfecting their
significantly contributed to our understanding of HS application in the challenging fields of pathobiology and
structure-function interrelationships. These advancements bioregulation.
have led to the development of HS-inspired drugs with
therapeutic applications in inflammation and cancer. 93 Acknowledgments
HS-mimetic glycopolymers hold promise for regulating We acknowledged the important contributions of the many
protein aggregation processes and may prevent the research scientists who have worked on various aspects of
development of neurodegenerative features in diseases the pathobiology of amyloid.
such as AD and PD. Funding
9. Conclusion This study was funded by the Melrose Personal Research

This review has highlighted the considerable complexity Fund, Sydney, Australia.
of HS in both normal and pathological tissues, which Conflict of interest
endows HSPGs with complex regulatory roles in
pathophysiology as well as essential instructive regulatory The authors declare no conflicts of interest.
properties in normal cellular processes. In pathological Author contributions
conditions, such as cancer and neurodegenerative
diseases, HSPGs contribute to the propagation of Conceptualization: All authors
abnormal protein aggregates in neural tissues, leading Writing – original draft: James Melrose
to disrupted neuronal function. These disruptions have Writing – review & editing: All authors
long-term neurotoxic consequences, including neuronal
death, cognitive decline, permanent memory loss, motor Ethics approval and consent to participate
impairment, and tissue dysfunction, as observed in AD Not applicable.
and PD. Factors such as sulfation position, charge
94
density, chain flexibility, and length, and the planar 3D Consent for publication
geometric presentation of sulfate groups all contribute Not applicable.
to HS’s interaction and its role in these processes.
Advanced techniques such as X-ray crystallography, Availability of data
in silico molecular docking, quantum semiconductor
bio-affinity nanoprobes, sub-nanometer ultra-high Not applicable.
resolution live cell imaging, single-cell transcriptomics, References
neutron scattering, and electron detachment dissociation
provide a sophisticated level of analysis. These techniques 1. Xie C, Schaefer L, Iozzo V. Global impact of proteoglycan
enhance our predictive capabilities in understanding science on human diseases. iScience. 2023;26(11):108095.
variations in HS conformation and their effects on doi: 10.1016/j.isci.2023.108095

Volume 3 Issue 3 (2024) 12 doi: 10.36922/an.3812