Brain α‐dystroglycan displays unique glycoepitopes and preferential binding to laminin‐10/11

McDearmon, Erin L.; Combs, Ariana C.; Sekiguchi, Kiyotoshi; Fujiwara, Hironobu; Ervasti, James M.

doi:10.1016/j.febslet.2006.05.010

Cited by 19 publications

(18 citation statements)

References 29 publications

(36 reference statements)

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“…They are also consistent with the findings that integrin-a3 is involved in the consolidation of LTP (Kramar et al, 2002). In addition to integrin, there are also non-integrin type of laminin receptors in the brain, such as the cellular prion protein (PrPc) (Graner et al, 2000) and a-dystroglycan (McDearmon et al, 2006). Further, PrPc-laminin interaction was shown to have a role in neuritogenesis in PC12 cells and memory consolidation in rats (Graner et al, 2000;Coitinho et al, 2006).…”

Section: Discussionsupporting

confidence: 83%

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

Yang

Liu

et al. 2011

Neuropsychopharmacol

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Laminin is a major structural element of the basal lamina consisting of an α-chain, a β-chain, and a γ-chain arranged in a cross-like structure, with their C-terminal inter-coiled. Laminin is abundantly expressed in the hippocampus of mature brain and is implicated in several psychiatric disorders, but its possible role involved in learning and memory function is not known. This issue was examined here. Our results revealed that water maze training significantly decreased laminin-β1 (LB1) expression in the rat hippocampal CA1 area. Transfection of LB1 WT plasmid to hippocampal CA1 neurons impaired water maze performance in rats. Meanwhile, it decreased the phosphorylation level of ERK/MAPK and protein kinase serum- and glucocorticoid-inducible kinase-1 (SGK1). By contrast, knockdown of endogenous LB1 expression using RNA interference (LB1 siRNA) enhanced water maze performance. Meanwhile, it increased the phosphorylation level of ERK/MAPK and SGK1. The enhancing effect of LB1 siRNA on spatial learning and on the phosphorylation of ERK/MAPK and SGK1 was blocked by co-treatment with the MEK inhibitor U0126 at a concentration that did not apparently affect spatial learning and ERK/MAPK phosphorylation alone. Further, the enhancing effect of LB1 siRNA on spatial learning and SGK1 phosphorylation was similarly blocked by co-transfection with SGK1 siRNA at a concentration that did not markedly affect spatial learning and SGK1 expression alone. These results together indicate that LB1 negatively regulates spatial learning in rats. In addition, LB1 impairs spatial learning through decreased activation of the ERK/MAPK-SGK1 signaling pathway in the rat hippocampus.

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Section: Discussionsupporting

confidence: 83%

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

Yang

Liu

et al. 2011

Neuropsychopharmacol

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“…The diversity of the O-glycan structures on α-DG allows α-DG to play distinct roles in various tissues to mediate the interactions with its variety of ligands. For example, HNK-1 epitope containing O-glycan mediates α-DG binding to laminins 10/11 in brain [32], while its core-1 structure of mucin-type glycan on α-DG mediates laminin-induced acetylcholine receptor clustering but not laminin binding activity in myotubes [33]. Our results suggested that the NeuAcα2-3Galβ1-4GlcNAcβ1-2Man glycan can not be the Large-induced functional glycans mediating laminin binding.…”

Section: Discussionmentioning

confidence: 76%

“…Galβ1-4(Fucα1-3)GlcNAcβ1-2Man (Lewis X structure) from sheep brain [30], HSO3-3GlcAβ1-4GlcNAcβ1-2Man (HNK1 epitope) from rat brain [31], [32], and Galβ1-3GalNAc (Core-1) from myotubes [33]. The diversity of the O-glycan structures on α-DG allows α-DG to play distinct roles in various tissues to mediate the interactions with its variety of ligands.…”

Section: Discussionmentioning

confidence: 99%

Large Induces Functional Glycans in an O-Mannosylation Dependent Manner and Targets GlcNAc Terminals on Alpha-Dystroglycan

et al. 2011

PLoS ONE

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Alpha-dystroglycan (α-DG) is a ubiquitously expressed receptor for extracellular matrix proteins and some viruses, and plays a pivotal role in a number of pathological events, including cancer progression, muscular dystrophies, and viral infection. The O-glycans on α-DG are essential for its ligand binding, but the biosynthesis of the functional O-glycans remains obscure. The fact that transient overexpression of LARGE, a putative glycosyltransferase, up-regulates the functional glycans on α-DG to mediate its ligand binding implied that overexpression of LARGE may be a novel strategy to treat disorders with hypoglycosylation of α-DG. In this study, we focus on the effects of stable overexpression of Large on α-DG glycosylation in Chinese hamster ovary (CHO) cell and its glycosylation deficient mutants. Surprisingly, stable overexpression of Large in an O-mannosylation null deficient Lec15.2 CHO cells failed to induce the functional glycans on α-DG. Introducing the wild-type DPM2 cDNA, the deficient gene in the Lec15.2 cells, fully restored the Large-induced functional glycosylation, suggesting that Large induces the functional glycans in a DPM2/O-mannosylation dependent manner. Furthermore, stable overexpression of Large can effectively induce functional glycans on N-linked glycans in the Lec8 cells and ldlD cells growing in Gal deficient media, in both of which circumstances galactosylation are deficient. In addition, supplement of Gal to the ldlD cell culture media significantly reduces the amount of functional glycans induced by Large, suggested that galactosylation suppresses Large to induce the functional glycans. Thus our results revealed a mechanism by which Large competes with galactosyltransferase to target GlcNAc terminals to induce the functional glycans on α-DG.

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“…This poor correlation (i.e. apparent severe depletion of IIH6 epitope also in patients with relatively milder variants) may be due to the fact that there is some laminin-binding activity on α-dystroglycan owing to other glycans that are not recognized by IIH6 (McDearmon et al , 1998, 2001, 2003, 2006; Stalnaker et al , 2010, 2011). Our genetic data (Fig.…”

Section: Discussionmentioning

confidence: 99%

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

Çırak

Foley

Herrmann

et al. 2013

Brain

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Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker–Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker–Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker–Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.

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Brain α‐dystroglycan displays unique glycoepitopes and preferential binding to laminin‐10/11

Cited by 19 publications

References 29 publications

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

Laminin-β1 Impairs Spatial Learning through Inhibition of ERK/MAPK and SGK1 Signaling

Large Induces Functional Glycans in an O-Mannosylation Dependent Manner and Targets GlcNAc Terminals on Alpha-Dystroglycan

ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies

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