Overexpression of glycogen synthase in mouse muscle results in less branched glycogen

Pederson, Bartholomew A.; Csitkovits, Anna G.; Simon, Renée; Schroeder, Jill M.; Wang, Wei; Skurat, Alexander V.; Roach, Peter J.

doi:10.1016/s0006-291x(03)00862-3

Cited by 26 publications

(23 citation statements)

References 19 publications

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“…A somewhat similar situation exists in glycogenosis type VII, Tarui disease, in which mutation of the phosphofructokinase gene causes a build-up of glycolytic intermediates that are thought to drive excessive glycogen synthesis through elevation of the allosteric activator of glycogen synthase, glucose-6-P (16). In addition, we observed that a mouse in which hyperactive glycogen synthase was overexpressed in muscle both overaccumulated glycogen and developed structures reminiscent of Lafora bodies (17,18). Therefore, several groups have looked for ways by which laforin could affect glycogen-synthesizing enzymes.…”

supporting

confidence: 64%

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Tagliabracci

Turnbull

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Lafora disease is a progressive myoclonus epilepsy with onset typically in the second decade of life and death within 10 years. Lafora bodies, deposits of abnormally branched, insoluble glycogen-like polymers, form in neurons, muscle, liver, and other tissues. Approximately half of the cases of Lafora disease result from mutations in the EPM2A gene, which encodes laforin, a member of the dual-specificity protein phosphatase family that additionally contains a glycogen binding domain. The molecular basis for the formation of Lafora bodies is completely unknown. Glycogen, a branched polymer of glucose, contains a small amount of covalently linked phosphate whose origin and function are obscure. We report here that recombinant laforin is able to release this phosphate in vitro, in a time-dependent reaction with an apparent Km for glycogen of 4.5 mg/ml. Mutations of laforin that disable the glycogen binding domain also eliminate its ability to dephosphorylate glycogen. We have also analyzed glycogen from a mouse model of Lafora disease, Epm2a ؊/؊ mice, which develop Lafora bodies in several tissues. Glycogen isolated from these mice had a 40% increase in the covalent phosphate content in liver and a 4-fold elevation in muscle. We propose that excessive phosphorylation of glycogen leads to aberrant branching and Lafora body formation. This study provides a molecular link between an observed biochemical property of laforin and the phenotype of a mouse model of Lafora disease. The results also have important implications for glycogen metabolism generally.polyglucosan ͉ Lafora bodies ͉ Epm2a ͉ phosphate

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supporting

confidence: 64%

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Tagliabracci

Turnbull

Wang

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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188

237

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“…The relative activities of glycogen synthase:GBE1 are likely to play a role in the overall degree of branching. In mice that overexpress glycogen synthase, glycogen is less branched and polyglucosan bodies develop (Raben et al 2001;Pederson et al 2003). Conversely, the absence of GBE1 activity observed in type IV glycogen storage disease results in poorly branched glycogen and polyglucosan bodies similar to those seen in Lafora disease (Moses and Parvari 2002).…”

mentioning

confidence: 98%

A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Cheng

Zhang²,

Gentry³

et al. 2007

Genes Dev.

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Cori's disease is a glycogen storage disorder characterized by a deficiency in the glycogen debranching enzyme, amylo-1,6-glucosidase,4-␣-glucanotransferase (AGL). Here, we demonstrate that the G1448R genetic variant of AGL is unable to bind to glycogen and displays decreased stability that is rescued by proteasomal inhibition. AGL G1448R is more highly ubiquitinated than its wild-type counterpart and forms aggresomes upon proteasome impairment. Furthermore, the E3 ubiquitin ligase Malin interacts with and promotes the ubiquitination of AGL. Malin is known to be mutated in Lafora disease, an autosomal recessive disorder clinically characterized by the accumulation of polyglucosan bodies resembling poorly branched glycogen. Transfection studies in HepG2 cells demonstrate that AGL is cytoplasmic whereas Malin is predominately nuclear. However, after depletion of glycogen stores for 4 h, ∼90% of transfected cells exhibit partial nuclear staining for AGL. Furthermore, stimulation of cells with agents that elevate cAMP increases Malin levels and Malin/AGL complex formation. Refeeding mice for 2 h after an overnight fast causes a reduction in hepatic AGL levels by 48%. Taken together, these results indicate that binding to glycogen crucially regulates the stability of AGL and, further, that its ubiquitination may play an important role in the pathophysiology of both Lafora and Cori's disease.

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“…For glycogen synthase, a low value is indicative of a highly phosphorylated enzyme. Branching enzyme activity was determined as previously described [26]. …”

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confidence: 99%

“…In this regard, it has been proposed that an imbalance between branching enzyme and glycogen synthase activities may cause the abnormal branching of the polyglucosan. In support of this idea, the GSL30 transgenic mouse that over-expresses constitutively active glycogen synthase in muscle hyper-accumulates glycogen that is less branched [26] and contains structures that resemble Lafora bodies [27]. One fundamental question yet to be answered is whether the activities of the glycogen metabolizing enzymes are affected in tissues that form Lafora bodies.…”

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confidence: 99%

Glycogen metabolism in tissues from a mouse model of Lafora disease

Wang

Lohi

Skurat

et al. 2007

Archives of Biochemistry and Biophysics

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Laforin, encoded by the EPM2A gene, by sequence is a member of the dual specificity protein phosphatase family. Mutations in the EPM2A gene account for around half of the cases of Lafora disease, an autosomal recessive neurodegenerative disorder, characterized by progressive myoclonus epilepsy. The hallmark of the disease is the presence of Lafora bodies, which contain polyglucosan, a poorly branched form of glycogen, in neurons, muscle and other tissues. Glycogen metabolizing enzymes were analyzed in a transgenic mouse over-expressing a dominant negative form of laforin that accumulates Lafora bodies in several tissues. Skeletal muscle glycogen was increased two-fold as was the total glycogen synthase protein. However, the −/+ glucose-6-P activity of glycogen synthase was decreased from 0.29 to 0.16. Branching enzyme activity was increased by 30%. Glycogen phosphorylase activity was unchanged. In whole brain, no differences in glycogen synthase or branching enzyme activities were found. Although there were significant differences in enzyme activities in muscle, the results do not support the hypothesis that Lafora body formation is caused by a major change in the balance between glycogen elongation and branching activities.Lafora disease is an autosomal recessive, progressive myoclonus epilepsy (OMIM #254780), with onset typically in teenagers followed by decline and death usually within ten years [1][2][3]. The disease is characterized by the presence of Lafora bodies, periodic acid-Schiff positive structures containing an abnormal form of glycogen, the branched polymer of glucose that serves as a stored form of glucose in many tissues. Although Lafora body formation in neurons is believed to account for the symptoms of the disease, the bodies are present in other tissues including liver, muscle and skin [4][5][6][7].Glycogen synthesis (Fig. 1) is mediated by glycogen synthase, which catalyzes formation of the predominant α-1,4-glycosidic linkage of the polymer and branching enzyme, which introduces the α-1,6-glycosidic branchpoints [8]. Degradation occurs in the cytosol through the action of glycogen phosphorylase and the debranching enzyme or alternatively in the lysosome via the activity of an α-glycosidase (acid maltase or GAA). In Lafora disease, a less ¶Correspondence to: Peter J. Roach, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202-5122, Phone 317 274-1582, FAX 317 274-4686, E-mail proach@iupui.edu. 1 Present address: Department of Medicine, University of California, San Diego, USA Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal di...

show abstract

Overexpression of glycogen synthase in mouse muscle results in less branched glycogen

Cited by 26 publications

References 19 publications

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo

A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease

Glycogen metabolism in tissues from a mouse model of Lafora disease

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