Protein aggregation diseases represent one of the most compelling research subjects both in protein chemistry and molecular medicine. Intracellular or extracellular deposits of misfolded and aggregated proteins are characteristic of protein aggregation diseases. Protein misfolding and abnormal aggregation are normally prevented by cellular quality-control mechanisms. Yet under certain circumstances, soluble proteins are converted into insoluble fibrils, which deposit as amyloid in organs such as the brain or liver. These unfavorable deposits in tissues are cleared by innate immune phagocytes such as microglia in the brain and macrophages in the peripheral tissues. Conversely, impairment of the cellular clearance leads to excess of deposits and disease progression.Since 1854 when Virchow introduced the term “amyloid”, which derives from the Latin amylum and Greek amylon, meaning starch, amyloid deposits were found to have a carbohydrate characteristic. Amyloid deposits in vivo are complex and contain not only the main protein fibrils but also non-protein constituents. These non-fibrillar components are also involved in the pathogenesis and progression of protein aggregation diseases. After first reporting the association of glycosaminoglycans (GAGs) with Amyloid-A amyloidosis by Snow and Kisilevsky in 1985, the associated GAG was further identified as heparan sulfate (HS).A multitude of studies have shown that HS coexists as a non-protein component in amyloid deposits in tissues1) and that HS in amyloid deposits is involved in inhibition of cellular clearance of amyloid deposits by forming a protective shield around them. HS has been known to interact with aggregation-prone peptides, including Amyloid ß (Aß) and tau in Alzheimer’s disease; α-synuclein in Parkinson’s disease; scrapie-type prion protein in Creutzfeldt–Jakob disease, Gerstmann–Sträussler–Scheinker syndrome, and scrapie; transthyretin in ATTR amyloidosis; islet amyloid polypeptide/amylin in type 2 diabetes mellitus1). Sulfate moieties of HS promote amyloid deposition by electrostatically interacting with amyloid fibrils or their precursors. The degree of HS sulfation is an important enhancer of Aβ amyloidosis. The location pattern of the negative charges of HS also determines how HS affects amyloidogenic proteins, supporting the idea that HS interacts with these proteins and amyloid through a specific sequence of HS functional domains. HS is a linear polysaccharide consisting of repeating disaccharide units of iduronic/glucuronic acid and glucosamine. The structure of HS is heterogeneous. The disaccharide units can be sulfated at different positions and extended up to 100 repeats. The highly sulfated domains of HS, S-domains, extend for 2-8 disaccharide units in length and are enriched in trisulfated disaccharide units [-iduronic acid (2S)-glucosamine (NS, 6S)–] (Figure 1). HS S-domains are selectively remodeled by Sulf2, an extracellular endoglucosamine 6-sulfatase2). S-domains are decisive for interactions between HS and its protein ligands. We showed that the HS S-domain mediates cytotoxicity of amyloid in culture, and that the detrimental effect was reduced by Sulf2 action3-5). HS S-domains have been implicated in the pathogenesis of various amyloid-associated diseases. We found that HS S-domains are selectively accumulated in Aß deposits in the brain of model mice (J20 and Tg2576 lines, Figure 2) and Figure 1. Highly sulfated domains (“S-domains”) of heparan sulfate (HS) and its remodeling by Sulf2Human Sulf2 consists of 870 amino acids and liberates C-6 sulfate groups of HS S-domains. Formylglycine modification is essential for the sulfatase activity. Furin cleavage regulates maturation of the Sulf2 protein.116Regulation of amyloid clearance byheparan sulfate remodelingKenji UchimuraUnit of Glycobiology Structure and Functions, CNRS, University of Lille, France
元のページ ../index.html#116