Midkine and multiple sclerosis Takeuchi, Hideyuki
British journal of pharmacology,
February 2014, Letnik:
171, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Multiple sclerosis (MS) is an autoimmune neurological disease characterized by inflammatory demyelination with subsequent neuronal damage in the CNS. MS and its animal model, experimental autoimmune ...encephalomyelitis (EAE), have been thought as autoreactive Th1 and Th17 cell‐mediated diseases. CD4+CD25+FoxP3+ regulatory T‐cell (Treg) plays a pivotal role in autoimmune tolerance, and tolerogenic dendritic cells (DCreg) drive the development of inducible Treg cells. Thus, a dysfunction in the development of Treg and DCreg leads to the development of autoimmune diseases. However, the factors that regulate Treg and DCreg are largely unknown. We recently showed that removal of midkine (MK) suppressed EAE due to an expansion of the Treg cell population as well as a decrease in the numbers of autoreactive Th1 and Th17 cells. MK decreased the Treg cell population by suppressing the phosphorylation of STAT5, which is essential for the expression of Foxp3, the master transcriptional factor of Treg cell differentiation. Furthermore, MK reduces the DCreg cell population by inhibiting the phosphorylation of STAT3, which is critical for DCreg development. Blockade of MK signalling by a specific RNA aptamer significantly elevated the population of DCreg and Treg cells and ameliorated EAE without detectable adverse effects. Therefore, the inhibition of MK may provide an effective therapeutic strategy against autoimmune diseases including MS.
Linked Articles
This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue‐4
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•Protein O-glucosylation on EGF repeats is essential for Notch signaling.•POGLUT1 recognizes the properly folded EGF repeats and O-gluco sylates the serine within the consensus ...sequence C1-X-S-X-(P/A)-C2.•XXYLT1 adds a terminal α3-linked Xyl to Xyl-Glc disaccharides on EGF repeats by an SNi-like retaining mechanism.•O-Fuc and O-Glc glycans stabilize EGF repeats, thereby regulating Notch trafficking.
Protein O-glucosylation is an unusual, linear trisaccharide form of O-glycosylation, xyloseα1-3xyloseα1-3glucose1β-O-serine, that is attached to epidermal growth factor-like (EGF) repeats found on numerous proteins including Notch. Genetic and biochemical studies have shown that protein O-glucosylation is essential for full Notch activity in Drosophila and mice. Aberrant protein O-glucosylation has been linked to human diseases. Structural studies of the glycosyltransferases, POGLUT1 and XXYLT1, in complex with substrates revealed the biosynthetic mechanisms of protein O-glucosylation. Very recently, two novel protein O-glucosyltransferases that modify sites distinct from POGLUT1 were identified. Furthermore, protein O-glucosylation turned out to modulate the stability of EGF repeats and thereby regulate Notch trafficking.
Significance of glycosylation in Notch signaling Takeuchi, Hideyuki; Haltiwanger, Robert S.
Biochemical and biophysical research communications,
10/2014, Letnik:
453, Številka:
2
Journal Article
Recenzirano
Odprti dostop
•Notch signaling is regulated by glycosylation of its extracellular domain.•Multiple O-linked carbohydrate modifications are found on the epidermal growth factor-like repeats of Notch.•Defects in ...glycosylation of Notch leads to a variety of human disorders.
Notch signaling is essential for cell-fate specification in metazoans, and dysregulation of the pathway leads to a variety of human diseases including heart and vascular defects as well as cancer. Glycosylation of the Notch extracellular domain has emerged as an elegant means for regulating Notch activity, especially since the discovery that Fringe is a glycosyltransferase that modifies O-fucose in 2000. Since then, several other O-glycans on the extracellular domain have been demonstrated to modulate Notch activity. Here we will describe recent results on the molecular mechanisms by which Fringe modulates Notch activity, summarize recent work on how O-glucose, O-GlcNAc, and O-GalNAc glycans affect Notch, and discuss several human genetic disorders resulting from defects in Notch glycosylation.
The central nervous system (CNS) has long been considered as an immunological privileged site where the surveillance of the immune system does not reach out. However, it is now recognized that this ...CNS homeostasis is collapsed by neuroinflammation such as influx of proinflammatory factors and cells, neuronal dysfunction, and glial activation. Currently, CNS neuroinflammation is considered as a main pathomechanism to mediate disease progression in not only neurotrauma and neuroinflammatory disorders but also neurodegenerative diseases including dementia. Moreover, growing evidence indicates that chronic CNS neuroinflammation is also involved in the pathogenesis of psychiatric disorders such as autism spectrum disorders, depression, and schizophrenia. This paper reviews the current proposed pathomechanisms and therapeutic strategies of neurological and psychiatric disorders from a point of view of chronic neuroinflammation.
This paper reviews the current proposed pathomechanisms and therapeutic strategies of neurological and psychiatric disorders from a point of view of chronic neuroinflammation.
Abstract Fingolimod phosphate (FTY720) is a sphingosine 1-phosphate (S1P) receptor agonist that is being used as a new oral drug for multiple sclerosis. FTY720 prevents lymphocytes from moving out of ...the lymphoid organs and inhibits autoreactive lymphocytes from infiltrating the central nervous system. Whether FTY720 directly affects microglia—the innate immune cells of the central nervous system—is unclear. Here we show that FTY720 binds S1P1 receptors to downregulate activated microglial production of such pro-inflammatory cytokines as tumor necrosis factor-α, interleukin-1β, and interleukin-6. FTY720 also upregulates microglial production of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor. These results suggested that FTY720 directly promotes the neuroprotective effects of microglia. Therefore, FTY720 may be a potent therapeutic agent for not only multiple sclerosis but also other neurologic diseases associated with microglial activation.
Notch signaling is an evolutionarily conserved signaling pathway and is essential for cell‐fate specification in metazoans. Dysregulation of Notch signaling results in various human diseases, ...including cardiovascular defects and cancer. In 2000, Fringe, a known regulator of Notch signaling, was discovered as a Notch‐modifying glycosyltransferase. Since then, glycosylation—a post‐translational modification involving literal sugars—on the Notch extracellular domain has been noted as a critical mechanism for the regulation of Notch signaling. Additionally, the presence of diverse O‐glycans decorating Notch receptors has been revealed in the extracellular domain epidermal growth factor‐like (EGF) repeats. Here, we concisely summarize the recent studies in the human diseases associated with aberrant Notch glycosylation.
Notch receptors are heavily decorated with structurally diverse glycans. Glycosylation of Notch extracellular domain has come to be noted as a critical mechanism for regulation of Notch signaling, and dysregulation of Notch signaling leads to various human diseases.
Protein glycosylation is a general post-translational modification pathway that controls various biological functions including protein trafficking, cell adhesion, and protein-ligand interaction ....
Traumatic brain injury (TBI) has been associated with the development of Alzheimer's disease (AD) because these conditions share common pathological hallmarks: amyloid-β and hyperphosphorylated tau ...accumulation. However, given recent data it is uncertain if a history of TBI leads to the development of AD. Moreover, chronic traumatic encephalopathy (CTE), caused by repetitive mild TBI and characterized by progressive neurodegeneration with hyperphosphorylated tau, has come to be recognized as distinct from AD. Therefore, it is important to elucidate the clinical outcomes and molecular mechanisms underlying tau pathology following TBI. We summarize the histopathological features and clinical course of TBI in CTE, comparing the tau pathology with that in AD. Following brain injury, diffuse axonal injury, and hyperphosphorylated tau aggregates are observed within a shorter period than in AD. Hyperphosphorylated tau deposition usually begins in the perivascular area of the sulci in the cerebral cortex, then spreads unevenly in the cortex in CTE, while AD shows diffuse distribution of hyperphosphorylated tau in the cortical areas. We also highlight the molecular profile of tau and the implications of tau progression throughout the brain in both diseases. Tau contains phosphorylation sites common to both conditions. In particular, phosphorylation at Thr
231
triggers a conformational change to the toxic
cis
form of tau, which is suggested to drive neurodegeneration. Although the mechanism of rapid tau accumulation remains unknown, the structural diversity of tau might result in these different outcomes. Finally, future perspectives on CTE in terms of tau reduction are discussed.
Microglia are resident immune cells in the central nervous system (CNS) that originate from myeloid progenitor cells in the embryonic yolk sac and are maintained independently of circulating ...monocytes throughout life. In the healthy state, microglia are highly dynamic and control the environment by rapidly extending and retracting their processes. When the CNS is inflamed, microglia can give rise to macrophages, but the regulatory mechanisms underlying this process have not been fully elucidated. Recent genetic studies have suggested that microglial function is compromised in Alzheimer's disease (AD), and that environmental factors such as diet and brain injury also affect microglial activation. In addition, studies of triggering receptor expressed on myeloid cells 2-deficiency in AD mice revealed heterogeneous microglial reactions at different disease stages, complicating the therapeutic strategy for AD. In this paper, we describe the relationship between genetic and environmental risk factors and the roles of microglia in AD pathogenesis, based on studies performed in human patients and animal models. We also discuss the mechanisms of inflammasomes and neurotransmitters in microglia, which accelerate the development of amyloid-β and tau pathology.
A genome-wide association study (GWAS) can be a powerful tool for the identification of genes associated with agronomic traits in crop species, but it is often hindered by population structure and ...the large extent of linkage disequilibrium. In this study, we identified agronomically important genes in rice using GWAS based on whole-genome sequencing, followed by the screening of candidate genes based on the estimated effect of nucleotide polymorphisms. Using this approach, we identified four new genes associated with agronomic traits. Some genes were undetectable by standard SNP analysis, but we detected them using gene-based association analysis. This study provides fundamental insights relevant to the rapid identification of genes associated with agronomic traits using GWAS and will accelerate future efforts aimed at crop improvement.
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