Abstract
Microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation, are two hallmarks of a family of neurodegenerative disorders collectively referred to as tauopathies. In many tauopathies, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP) and Pick’s disease, tau aggregates are found associated with highly sulfated polysaccharides known as heparan sulfates (HSs). In AD, amyloid beta (Aβ) peptide aggregates associated with HS are also characteristic of disease. Heparin, an HS analog, promotes misfolding, hyperphosphorylation and aggregation of tau protein in vitro. HS also provides cell surface receptors for attachment and uptake of tau seeds, enabling their propagation. These findings point to HS-tau interactions as potential therapeutic targets in tauopathies. The zebrafish genome contains genes paralogous to MAPT, genes orthologous to HS biosynthetic and chain modifier enzymes, and other genes implicated in AD. The nervous system in the zebrafish bears anatomical and chemical similarities to that in humans. These homologies, together with numerous technical advantages, make zebrafish a valuable model for investigating basic mechanisms in tauopathies and identifying therapeutic targets. Here, we comprehensively review current knowledge on the role of HSs in tau pathology and HS-targeting therapeutic approaches. We also discuss novel insights from zebrafish suggesting a role for HS 3-O-sulfated motifs in tau pathology and establishing HS antagonists as potential preventive agents or therapies for tauopathies.
Highlights
Reviewed by: Caghan Kizil, Helmholtz-Gemeinschaft Deutscher Forschungszentren (HZ), Germany Monica Ryff Moreira Roca Vianna, Pontifícia Universidade Católica do
Tauopathies are neurodegenerative disorders characterized by microtubule-associated protein tau (MAPT) hyperphosphorylation and aggregation into paired helical filaments (PHFs) or straight filaments (SFs), forming neurofibrillary tangles (NFTs) in brain
Hasegawa et al (1997), have suggested that sequence differences among moderately sulfated GAGs likely play a role in their interaction with tau (Hasegawa et al, 1997), as the overall level of sulfation cannot account for the observed effects
Summary
Glycosaminoglycans (GAGs), formerly called mucopolysaccharides, are a major class of anionic polysaccharides, consisting of unbranched and often long polysaccharide chains made of disaccharide units. Zebrafish 2-OST or HS2ST is expressed in all brain regions in early developmental stages. 3ost RNAs are maternally expressed and ubiquitously accumulated in early cleavage stage embryos, before being transcribed in midbrain, hindbrain, olfactory epithelium and otic vesicle by 48 hpf onward. The 3ost gene is expressed during early cleavage stages and becomes restricted to brain neurons by 48 hpf (Cadwallader and Yost, 2006a). Heparan sulfate PGs (HSPGs) comprise one or more HSsulfated GAG chains covalently linked to a core protein. The sulfation pattern of HSPGs, which is more diverse than other GAG chain modifications, plays an essential role in the specificity of the binding sites of HSPGs to heparinbinding proteins (Aviezer et al, 1994; Sanderson et al, 1994; Herndon et al, 1999). Complete knowledge of the PG interactome promotes development of specific therapies targeting harmful intractions and/or enhancing beneficial ones
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