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REVIEW

Heparan sulfate proteoglycans in pathological protein aggregation and brain functionality

James Melrose1,2,3* ,  Margaret M. Smith2
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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
Advanced Neurology 2024, 3(3), 3812 https://doi.org/10.36922/an.3812
Submitted: 31 May 2024 | Accepted: 23 July 2024 | Published: 28 August 2024
© 2024 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
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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 nervous system. These pathological developments lead to impaired cognition, permanent memory loss in dementia and AD, and an inability of the brain to exert normal neuromuscular control, affecting motor functions and body movement in PD. A deeper understanding of the properties of HS in these degenerative processes is essential for the development of therapeutic measures to treat these conditions. Significant improvements in neuroimaging, next-generation glycosaminoglycan analytical techniques, and functional glycomics hold great promise for elucidating the complexities of HS structure and function. These advancements may significantly aid in the development of HS biotherapeutics to treat these debilitating conditions, which are increasingly impacting the aging global population. While a number of promising therapeutic candidates have already emerged, further research is required to optimize their biotherapeutic applications in this challenging area of pathobiology, bioregulation, and the recovery of neural function.

Keywords
Amyloid
Heparan sulfate proteoglycans
Synuclein
Prion
Tau
Alzheimers disease
Parkinsons disease
Neurocognitive decline
Funding
This study was funded by the Melrose Personal Research Fund, Sydney, Australia.
Conflict of interest
The authors declare no conflicts of interest.
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