Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer’s pathology

Zhang, Zui; Takeda-Uchimura, Yoshiko; Foyez, Tahmina; Ohtake-Niimi, Shiori; Narentuya,; Akatsu, Hiroyasu; Nishitsuji, Kazuchika; Michikawa, Makoto; Wyss‐Coray, Tony; Kadomatsu, Kenji; Uchimura, Kenji

doi:10.1073/pnas.1615036114

Cited by 41 publications

(40 citation statements)

References 53 publications

(76 reference statements)

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“…Phosphacan is present in early postnatal brains in mice, the 5D4 epitope on KS requires the action of the sulfotransferase GlcNAc6ST1 (Hoshino et al 2014), and this mitigates AD pathology (Zhang et al 2017). GlcNAc6ST1 is up-regulated in the brains of J20 and Tg2576 Tg mice and AD patients correlating with increased levels of 125-190 kDa KSPGs, control tissues however contain > 460-kDa KSPGs (Zhang et al 2017). A better understanding of the cell types that produce these KS species may explain the molecular mechanisms that underlie microglial activation and neurodegenerative processes in AD.…”

Section: Phosphacan/receptor Protein Tyrosine Phosphatase-f and Theirmentioning

confidence: 99%

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

Melrose

2019

Journal of Neurochemistry

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Compared to the other classes of glycosaminoglycans (GAGs), that is, chondroitin/dermatan sulfate, heparin/heparan sulfate and hyaluronan, keratan sulfate (KS), have the least known of its interactive properties. In the human body, the cornea and the brain are the two most abundant tissue sources of KS. Embryonic KS is synthesized as a linear poly‐N‐acetyllactosamine chain of d‐galactose‐GlcNAc repeat disaccharides which become progressively sulfated with development, sulfation of GlcNAc is more predominant than galactose. KS contains multi‐sulfated high‐charge density, monosulfated and non‐sulfated poly‐N‐acetyllactosamine regions and thus is a heterogeneous molecule in terms of chain length and charge distribution. A recent proteomics study on corneal KS demonstrated its interactivity with members of the Slit‐Robbo and Ephrin‐Ephrin receptor families and proteins which regulate Rho GTPase signaling and actin polymerization/depolymerization in neural development and differentiation. KS decorates a number of peripheral nervous system/CNS proteoglycan (PG) core proteins. The astrocyte KS‐PG abakan defines functional margins of the brain and is up‐regulated following trauma. The chondroitin sulfate/KS PG aggrecan forms perineuronal nets which are dynamic neuroprotective structures with anti‐oxidant properties and roles in neural differentiation, development and synaptic plasticity. Brain phosphacan a chondroitin sulfate, KS, HNK‐1 PG have roles in neural development and repair. The intracellular microtubule and synaptic vesicle KS‐PGs MAP1B and SV2 have roles in metabolite transport, storage, and export of neurotransmitters and cytoskeletal assembly. MAP1B has binding sites for tubulin and actin through which it promotes cytoskeletal development in growth cones and is highly expressed during neurite extension. The interactive capability of KS with neuroregulatory ligands indicate varied roles for KS‐PGs in development and regenerative neural processes.

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Section: Phosphacan/receptor Protein Tyrosine Phosphatase-f and Theirmentioning

confidence: 99%

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

Melrose

2019

Journal of Neurochemistry

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Section: Keratan Sulfatementioning

confidence: 97%

“…Another report about the involvement of KS chains in diseases describes modified KS glycans in Alzheimer pathology (Lindahl et al 1996;Zhang et al 2017). The sulfotransferase GlcNAc6ST1 was found to be upregulated in the brains of transgenic mouse models (J20 and Tg2576) and of patients with Alzheimer disease (Zhang et al 2017). KS chains have also been found to play key roles in the early phase of amyotrophic lateral sclerosis (ALS) (Hirano et al 2013), a motor neurondegenerative disease that leads to progressive muscle weakness and complete paralysis within 1 to 5 years after disease onset.…”

Section: Keratan Sulfatementioning

confidence: 99%

Chondroitin, Dermatan, Heparan, and Keratan Sulfate: Structure and Functions

Bedini

Corsaro

Fernández‐Mayoralas

et al. 2019

Biologically-Inspired Systems

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Sulfated glycosaminoglycans (heparan sulfate, chondroitin sulfate, dermatan sulfate, and keratan sulfate) are a family of complex polysaccharides ubiquitously, but not exclusively, distributed among mammals, found both in extracellular matrices and on cell surfaces. They play key roles in a myriad of physiological and pathological processes, including, among others, angiogenesis, cancer, immunity, and infectious diseases. Here the main issues concerning their chemical structure, biosynthesis, extraction, and purification from natural sources, structural characterization, as well as their most important biological functions are discussed.

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“…Also, studies indicated CSF IgG N-glycosylation as a potential biomarker for ALS. Furthermore, a carbohydrate sulfotransferase, GlcNAc6ST1, is upregulated and identified as one of the top 40 ALS relevant genes in microglia [116]. In addition, the concentration of CML, one of the prominent AGEs, significantly elevated in the CSF of ALS patients [117].…”

Section: Glycans and Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

et al. 2019

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Neurodegenerative diseases (NDs) affect millions of people worldwide. Characterized by the functional loss and death of neurons, NDs lead to symptoms (dementia and seizures) that affect the daily lives of patients. In spite of extensive research into NDs, the number of approved drugs for their treatment remains limited. There is therefore an urgent need to develop new approaches for the prevention and treatment of NDs. Glycans (carbohydrate chains) are ubiquitous, abundant, and structural complex natural biopolymers. Glycans often covalently attach to proteins and lipids to regulate cellular recognition, adhesion, and signaling. The importance of glycans in both the developing and mature nervous system is well characterized. Moreover, glycan dysregulation has been observed in NDs such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Therefore, glycans are promising but underexploited therapeutic targets. In this review, we summarize the current understanding of glycans in NDs. We also discuss a number of natural products that functionally mimic glycans to protect neurons, which therefore represent promising new therapeutic approaches for patients with NDs.

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Deficiency of a sulfotransferase for sialic acid-modified glycans mitigates Alzheimer’s pathology

Cited by 41 publications

References 53 publications

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

Keratan sulfate (KS)‐proteoglycans and neuronal regulation in health and disease: the importance ofKS‐glycodynamics and interactive capability with neuroregulatory ligands

Chondroitin, Dermatan, Heparan, and Keratan Sulfate: Structure and Functions

Glycan Mimetics from Natural Products: New Therapeutic Opportunities for Neurodegenerative Disease

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