The role of heparan sulfates in protein aggregation and their potential impact on neurodegeneration

Abstract

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and prion diseases, are directly linked to the formation and accumulation of protein aggregates in the brain. These aggregates, principally made of proteins or peptides that clamp together after acquisition of β-folded structures, also contain heparan sulfates. Several lines of evidence suggest that heparan sulfates centrally participate in the protein aggregation process. In vitro, they trigger misfolding, oligomerization, and fibrillation of amyloidogenic proteins, such as Aβ, tau, α-synuclein, prion protein, etc. They participate in the stabilization of protein aggregates, protect them from proteolysis, and act as cell-surface receptors for the cellular uptake of proteopathic seeds during their spreading. This review focuses attention on the importance of heparan sulfates in protein aggregation in brain disorders including Alzheimer's, Parkinson's, and prion diseases. The presence of these sulfated polysaccharides in protein inclusions in vivo and their capacity to trigger protein aggregation in vitro strongly suggest that they might play critical roles in the neurodegenerative process. Further advances in glyco-neurobiology will improve our understanding of the molecular and cellular mechanisms leading to protein aggregation and neurodegeneration.

A Connected Network of Interacting Proteins Is Involved in Human-Tau Toxicity in Drosophila

“…Tagging modules with GO terms also outlined cell cycle activities (module 6), RNA metabolism (clusters 3 and 5) and Heparan sulfate proteoglycan (HSPGs) biosynthesis (module 8). Interestingly, many of these processes are in agreement with Tau physiological and pathological functions (Hannan et al, 2016;Sotiropoulos et al, 2017;Zhou et al, 2017;Maïza et al, 2018).…”

The Non-Fibrillating N-Terminal of α-Synuclein Binds and Co-Fibrillates with Heparin

“…A key observation made in this work was that heparin at low concentrations bound to the N-terminal of aSN and induced type-I β-turn structures that are likely a key passageway for entering the fibrillation pathway. Thus, heparan sulfates of the cell surface HSPGs may not only internalize the fibrillar aggregates but also stabilize and/or induce the initial fibrillation-prone states [ 90 ]. If this is indeed so, and this fibrillation triggering also happens in vivo, then the type-I β-turn structures constitute a scaffold for potential targeting by small molecule drugs to be further used therapeutically.…”

The Role of Glial Mitochondria in α-Synuclein Toxicity

“…Several papers have shown that the aggregation of α-syn is accelerated by heparin and heparan sulfate (HS; Cohlberg et al, 2002;Ihse et al, 2017;Maiza et al, 2018). HS is a linear polysaccharide expressed on the cell surface or as an extracellular matrix protein (Iozzo, 1998;Medeiros, 2000).…”

“…Heparan sulfate proteoglycans (HSPGs) are internalized by α-syn in the MO3.13 human oligodendrocyte cell line (Ihse et al, 2017). Furthermore, the presence of HSPGs initiates a conformational change in α-syn forms a native state into an oligomeric state, including β-sheet formation, through protein unfolding (Motamedi-Shad et al, 2009;Maiza et al, 2018). Aggregate α-syn uptake relies on HS by binding to the plasma membrane (Holmes et al, 2013;Ihse et al, 2017).…”