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Advanced Neurology

REVIEW ARTICLE
Heparan sulfate proteoglycans in pathological

protein aggregation and brain functionality

James Melrose 1,2,3 * and Margaret M. Smith 2
1 Graduate School of Biomedical Engineering, Faculty of Engineering, University of New South
Wales, Sydney, New South Wales, Australia
2 Raymond Purves Laboratory, Institute of Bone and Joint Research, Kolling Institute of Medical
Research, Northern Sydney Local Health District, Royal North Shore Hospital, St. Leonard’s, New
South Wales, Australia
3 Sydney Medical School, Northern Clinical School, University of Sydney at Royal North Shore
Hospital, St. Leonard’s, New South Wales, Australia

Abstract

Proteoglycans are highly specialized proteins with specific interactive modules in their
core proteins, allowing them to engage with a diverse range of cellular and structural
proteins, contributing to many varied roles in cell processes. This review examines the
roles of heparan sulfate (HS) proteoglycans (HSPGs) in the assembly of pathological
protein aggregates in brain tissues, which negatively impact cognitive brain function.
While HSPGs play roles in normal brain development, they also contribute to the
abnormal accumulation and persistence of protein aggregates in Alzheimer’s and
Parkinson’s diseases (AD and PD), prolonging their neurotoxic effects. HSPG-mediated
effects on the innate immune system may also contribute to the development of
neuroinflammation and pathogenesis of neurodegenerative changes in the central
*Corresponding author: nervous system. These pathological developments lead to impaired cognition,
James Melrose permanent memory loss in dementia and AD, and an inability of the brain to exert
(james.melrose@sydney.edu.au) normal neuromuscular control, affecting motor functions and body movement in
Citation: Melrose J, Smith MM. PD. A deeper understanding of the properties of HS in these degenerative processes
Heparan sulfate proteoglycans in is essential for the development of therapeutic measures to treat these conditions.
pathological protein aggregation
and brain functionality. Adv Neuro. Significant improvements in neuroimaging, next-generation glycosaminoglycan
2024;3(3):3812. analytical techniques, and functional glycomics hold great promise for elucidating
doi: 10.36922/an.3812 the complexities of HS structure and function. These advancements may significantly
Received: May 31, 2024 aid in the development of HS biotherapeutics to treat these debilitating conditions,
which are increasingly impacting the aging global population. While a number of
Accepted: July 23, 2024
promising therapeutic candidates have already emerged, further research is required
Published Online: August 28, 2024 to optimize their biotherapeutic applications in this challenging area of pathobiology,
Copyright: © 2024 Author(s). bioregulation, and the recovery of neural function.
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution Keywords: Amyloid; Heparan sulfate proteoglycans; Synuclein; Prion; Tau; Alzheimers
License, permitting distribution, disease; Parkinsons disease; Neurocognitive decline
and reproduction in any medium,
provided the original work is
properly cited.
Publisher’s Note: AccScience
Publishing remains neutral with 1. Introduction
regard to jurisdictional claims in
published maps and institutional Proteoglycans are highly specialized proteins encoded by a small fraction of the
affiliations. human genome, with approximately 0.25% of all protein-encoding genes responsible

Volume 3 Issue 3 (2024) 1 doi: 10.36922/an.3812