Extracellular matrix heparan sulfate proteoglycan (HSPG)

Extracellular matrix heparan sulfate proteoglycans (HSPGs) are complex macromolecules consisting of a core protein covalently linked to heparan sulfate glycosaminoglycan chains. In the context of neurodegenerative and systemic metabolic diseases, HSPGs like perlecan and agrin are consistently found co-localized with amyloid deposits, where they play a critical role in the pathogenesis of amyloidosis. They act as molecular scaffolds that promote the aggregation of amyloidogenic proteins, such as amyloid-beta or amylin, and protect the resulting fibrils from proteolytic degradation, thereby stabilizing the plaques. Because of this essential role in fibrillogenesis and plaque maintenance, HSPGs have emerged as significant therapeutic targets. Drugs designed to target this interaction, such as small-molecule sulfonated or sulfated compounds, aim to competitively inhibit the binding of HSPGs to amyloid peptides, effectively preventing fibril formation and facilitating the clearance of existing deposits. However, therapeutic development is challenged by the need to avoid disrupting the vital physiological roles of HSPGs in cell signaling and tissue architecture.

Other names

Heparan sulfate proteoglycanAmyloid-associated heparan sulfate proteoglycanPerlecanAgrinSyndecanGlypicanBasement membrane-specific heparan sulfate proteoglycan core protein

Competitive inhibition of the binding between heparan sulfate proteoglycans and amyloidogenic proteins to prevent fibril formation and stabilization.