The sulfation code for propagation of neurodegeneration

Abstract

Edited by Paul E. Fraser Prion-like propagation of protein aggregates is thought to be an essential feature in many neurodegenerative diseases, but the mechanisms underlying transcellular transfer of protein aggregates remain unclear. Stopschinski et al. now demonstrate that the cellular uptake of tau, A␤, and ␣-synuclein aggregates mediated by heparan sulfate proteoglycans (HSPGs) varies with distinct glycosaminoglycan chain length and sulfation patterns. The results help us to understand how different protein aggregates propagate, leading to distinct neurodegenerative pathologies.Prion diseases are a group of fatal transmissible neurodegenerative diseases characterized by the accumulation of an abnormal form of prion protein (PrP Sc ) in the central nervous system (CNS).2 Prion diseases are transmissible interindividually, crossing even species barriers, and propagate intraindividually. Similar to prion diseases, many neurodegenerative diseases are also characterized by the accumulation of abnormal proteins in the CNS including ␤-amyloid protein (A␤) and tau in Alzheimer's disease (AD), tau in non-AD tauopathies, ␣-synuclein in Lewy body diseases such as Parkinson's disease and dementia with Lewy bodies, and transactive response DNAbinding protein 43 kDa (TDP-43) in frontotemporal dementia and amyotrophic lateral sclerosis (1-3). Increasing evidence from experimental studies has indicated that misfolded aggregated proteins in these diseases have prion-like properties: They propagate through neuronal networks or other pathways in the CNS of individuals and also cause interindividual transmission of these diseases. In human studies, neurodegeneration seems to progress along the neuronal networks by propagation of protein aggregates in the CNS, although evidence for human-to-human transmission is still limited (4, 5).For intercellular propagation of intracellular protein aggregates, release of aggregates from donor cells and uptake of aggregates by recipient cells are essential steps, followed by intracellular seeding in the recipient cells. In transcellular transfer of protein aggregates, multiple mechanisms have been proposed: 1) extracellular vesicles like exosomes and ectosomes reaching the cytoplasm of recipient cells by fusion, 2) free protein aggregates exocytosed from donor cells taken up by recipient cells with receptor-or nonreceptor-mediated endocytosis/macropinocytosis, and 3) transfer through nanotubes, although it remains unclear which is the main mechanism for transcellular transfer of certain protein aggregates in certain areas of the CNS.Diamond and colleagues (6) have focused on heparan sulfate proteoglycans (HSPGs) on the cell surface as receptors for uptake of protein aggregates such as A␤, tau, and ␣-synuclein. They previously observed that cellular uptake and consequent intracellular seeding of tau and ␣-synuclein fibrils require HSPGs, similar to results from another study (7). Inhibition of the interaction with HSPGs blocked transcellular aggregate propagation, indicating that the interact...

Extracellular Monomeric Tau Is Internalized by Astrocytes

“…Tau can be internalized by glial cells through several mechanisms (Leyns and Holtzman, 2017). In this regard, Tau aggregates are taken up by cultured cells, primary neurons, and brain through heparan sulfate proteoglycans (HSPGs) (Holmes et al, 2013; Stopschinski et al, 2018; Yamada and Hamaguchi, 2018). Furthermore, Tau fibril species are internalized in astrocytes via the lysosomal pathway (Martini-Stoica et al, 2018).…”

Sulfation Patterns of Saccharides and Heavy Metal Ion Binding

“…[1] However, understanding the specific interactions of each component of the ECM constitutesamajor challenge. [4][5][6] Given that sulfated saccharides exist in metal-ion-rich environments, they interact with, absorb, and store av ariety of metal ions. Sulfated saccharides such as glycosaminoglycans (GAG) and carrageenans are major components of the ECM of organismsf rom animals to algae.…”

“…[2,3] These molecules have a large variety of sulfationp atterns that affect their structural properties and biologicala ctivities. [4][5][6] Given that sulfated saccharides exist in metal-ion-rich environments, they interact with, absorb, and store av ariety of metal ions. [7][8][9] Metal ion binding to saccharides can result in changes of the physical properties and the biological interactions of these saccharides and can lead to the accumulation of both essential and toxic heavym etal ions.…”

“…Sulfated saccharides such as glycosaminoglycans (GAG) and carrageenans are major components of the ECM of organisms from animals to algae . These molecules have a large variety of sulfation patterns that affect their structural properties and biological activities . Given that sulfated saccharides exist in metal‐ion‐rich environments, they interact with, absorb, and store a variety of metal ions .…”

A novel exchange method to access sulfated molecules

“…Organosulfates and sulfamates contain polar functional groups that are important for the study of molecular interactions in the life sciences, such as: neurodegeneration 1 ; plant biology 2 ; neural stem cells 3 ; heparan binding 4 ; and viral infection 5 . Recent total syntheses including 11-saxitoxinethanoic acid 6 , various saccharide assemblies 7 – 10 , and seminolipid 11 have all relied on the incorporation of a highly polar organosulfate motif.…”