Distinct Structures and Functions of Related Pre- and Postsynaptic Carbohydrates at the Mammalian Neuromuscular Junction

Neuromuscular Disorders

2007

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Overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) in the skeletal muscles of transgenic mdx mice inhibits the development of muscular dystrophy. The profound effect of Galgt2 on muscular dystrophy in transgenic mice, where overexpression is begins from embryonic stages, is complicated by its additional effects on muscle growth and neuromuscular structure. Here, we use Adeno-associated virus (AAV) to show that overexpression of Galgt2 in skeletal myofibers in the early postnatal period is equally effective in inhibiting muscular dystrophy, but that it does so without altering muscle growth or neuromuscular structure. Unlike embryonic overexpression, postnatal overexpression of Galgt2 did not reproducibly increase the expression of utrophin, synaptic laminins, or dystrophin-associated glycoproteins along infected myofibers. Moreover, Galgt2 overexpression inhibited muscular dystrophy to the same extent in utrophin-deficient mdx muscles as it did in utrophin-expressing mdx muscles. Thus, Galgt2 is a molecular target for therapy in DMD that can be utilized in a manner that separates its clinical benefit from its effects on development, and its clinical benefit is distinct from that achieved by utrophin.

Section: Lack Of Galgt2 Effect On Muscle Growth and Neuromuscular Strsupporting

confidence: 65%

“…One of these neuromuscular proteins is utrophin, a closely related homologue of dystrophin [7]. Another neuromuscular component is the cytotoxic T cell (CT) carbohydrate [8].…”

Section: Introductionmentioning

confidence: 99%

Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: Evidence for a utrophin-independent mechanism

Camboni

Neuromuscular Disorders

2007

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“…WFA staining is analogous to staining with the CT2 anti-CT glycan antibody, which also recognizes increased GALGT2-dependent muscle glycosylation. 27 For all three treated muscles (gastroc, quad, and TA), we observed that most myofibers overexpressed GALGT2 activity. Here again, this percentage declined at 3 and 6 months after treatment, with only 20% to 35% of myofibers maintaining CT glycan overexpression at 6 months after treatment.…”

Section: Fkrp Surrogate Gene Therapymentioning

confidence: 67%

“…We used WFA, a bGalNAc binding lectin that recognizes the CT glycan made by GALGT2, 27 and WGA, a non-GalNAc binding lectin known to precipitate non-CT glycosylated a dystroglycan. 6 We precipitated differing amounts of NP-40esolubilized muscle protein lysate to determine the extent of GALGT2-dependent glycosylation in treated and untreated FKRP P448Lneo À muscles.…”

Section: Effect Of Raavrh74mckgalgt2 Treatment On a Dystroglycan Exmentioning

confidence: 99%

B4GALNT2 (GALGT2) Gene Therapy Reduces Skeletal Muscle Pathology in the FKRP P448L Mouse Model of Limb Girdle Muscular Dystrophy 2I

Thomas

The American Journal of Pathology

2016

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Overexpression of B4GALNT2 (previously GALGT2) inhibits the development of muscle pathology in mouse models of Duchenne muscular dystrophy, congenital muscular dystrophy 1A, and limb girdle muscular dystrophy 2D. In these models, muscle GALGT2 overexpression induces the glycosylation of a dystroglycan with the cytotoxic T cell glycan and increases the overexpression of dystrophin and laminin a2 surrogates known to inhibit disease. Here, we show that GALGT2 gene therapy significantly reduces muscle pathology in FKRP P448Lneo À mice, a model for limb girdle muscular dystrophy 2I. rAAVrh74.MCK.GALGT2-treated FKRP P448Lneo À muscles showed reduced levels of centrally nucleated myofibers, reduced variance, increased size of myofiber diameters, reduced myofiber immunoglobulin G uptake, and reduced muscle wasting at 3 and 6 months after treatment. GALGT2 overexpression in FKRP P448Lneo À muscles did not cause substantial glycosylation of a dystroglycan with the cytotoxic T cell glycan or increased expression of dystrophin and laminin a2 surrogates in mature skeletal myofibers, but it increased the number of embryonic myosin-positive regenerating myofibers. These data demonstrate that GALGT2 overexpression can reduce the extent of muscle pathology in FKRP mutant muscles, but that it may do so via a mechanism that differs from its ability to induce surrogate gene expression. (Am J Pathol 2016 http://dx

“…6,31 These glycan sequences include additional modifications of the O-linked mannose structure NeuAcα2,3Galβ1,4GlcNAcβ1,2Manα-O-S/ T, such as addition of terminal β1,4GalNAc to create the CT carbohydrate antigen, which is found at the neuromuscular junction, 41 addition of β1,6-linked sialyl-N-acetyllactosamine to create branched O-mannose structures, addition of the sulfated glucuronic acid to create the HNK-1 carbohydrate, or fucosylation to create the Lewis X antigen. Additional structures that are O-linked to GalNAc might also be present (Figure 2).…”

Section: Glycosylation Of Dystroglycanmentioning

confidence: 99%

Mechanisms of Disease: congenital muscular dystrophies—glycosylation takes center stage

2006

Nat Rev Neurol

SUMMARYRecent studies have defined a group of muscular dystrophies, now termed the dystroglycanopathies, as novel disorders of glycosylation. These conditions include Walker-Warburg syndrome, muscleeye-brain disease, Fukuyama-type congenital muscular dystrophy, congenital muscular dystrophy types 1C and 1D, and limb-girdle muscular dystrophy type 2I. Although clinical findings can be highly variable, dystroglycanopathies are all characterized by cortical malformations and ocular defects at the more severe end of the clinical spectrum, in addition to muscular dystrophy. All of these disorders are defined by the underglycosylation of α-dystroglycan. Defective glycosylation of dystroglycan severs the link between this important cell adhesion molecule and the extracellular matrix, thereby contributing to cellular pathology. Recent experiments indicate that glycosylation might not only define forms of muscular dystrophy but also provide an avenue to the development of therapies for these disorders.