Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy

Chan, Elayne M.; Ackerley, Cameron; Lohi, Hannes; Ianzano, Leonarda; Cortez, Miguel A.; Shannon, Patrick; Scherer, Stephen W.; Minassian, Berge A.

doi:10.1093/hmg/ddh130

Cited by 105 publications

(105 citation statements)

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“…To evaluate whether there were gross impairments of glycogen metabolism in a mouse model of Lafora disease, we took advantage of the Cys266Ser laforin over-expressing mice [13]. These animals form Lafora bodies in both muscle and neurons.…”

Section: Resultsmentioning

confidence: 99%

“…Mice over-expressing mutant laforin, described in the Introduction, had gene expression driven by the β-actin promoter [13].…”

Section: Methodsmentioning

confidence: 99%

“…Two mouse models of Lafora disease have been developed [13,25]. Disruption of the mouse Epm2a gene resulted in viable homozygous null mice that accumulated structures similar to Lafora bodies in neurons and other tissues [25].…”

Section: Nih Public Accessmentioning

confidence: 99%

“…PTG has been proposed to act as a scaffold, binding also to glycogen synthase, phosphorylase and phosphorylase kinase [24]. Fernandez-Sanchez et al [18] found that a disease-associated mutation of laforin, G240S, has no effect on either phosphatase activity or glycogen binding but impairs interaction with PTG.Two mouse models of Lafora disease have been developed [13,25]. Disruption of the mouse Epm2a gene resulted in viable homozygous null mice that accumulated structures similar to Lafora bodies in neurons and other tissues [25].…”

mentioning

confidence: 99%

“…Behavioral abnormalities were detected at 4 months and by 9 months the animals had myoclonic seizures, ataxia and epileptiform electroencephelogram activity. The second mouse model utilized transgenic over-expression of a dominant negative form of laforin generated by mutating the catalytic Cys266 to Ser [13]. The mice developed Lafora bodies in muscle, liver and neurons and, by immunogold electron microscopy, laforin was shown to be in proximity of the polyglucosan deposits.…”

mentioning

confidence: 99%

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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...

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Section: Resultsmentioning

confidence: 99%

“…Mice over-expressing mutant laforin, described in the Introduction, had gene expression driven by the β-actin promoter [13].…”

Section: Methodsmentioning

confidence: 99%