ArticleThe Journal of biological chemistry2012
Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 47 citations in OpenAlex.
- Solving the Insoluble: Regulation of α-Polyglucan Solubility and Functionality in Nature.Molecules (Basel, Switzerland) · 2026Review
- Lafora disease gene therapy: EPM2A but not EPM2B overexpression results in Lafora body formation.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- Lafora Disease: A Case Report and Evolving Treatment Advancements.Brain sciences · 2023Article
- Lafora disease: Current biology and therapeutic approaches.Revue neurologique · 2022Review
- Trehalose Ameliorates Seizure Susceptibility in Lafora Disease Mouse Models by Suppressing Neuroinflammation and Endoplasmic Reticulum Stress.Molecular neurobiology · 2021Article
- Polyglucosan body structure in Lafora disease.Carbohydrate polymers · 2020Article
- Targeting Pathogenic Lafora Bodies in Lafora Disease Using an Antibody-Enzyme Fusion.Cell metabolism · 2019Article
- Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases.Cell reports · 2019Article
- Brain Glycogen Structure and Its Associated Proteins: Past, Present and Future.Advances in neurobiology · 2019Review
- Lafora disease - from pathogenesis to treatment strategies.Nature reviews. Neurology · 2018Review
- Lafora disease: from genotype to phenotype.Journal of genetics · 2018Review
- Cardiomyopathy as presenting sign of glycogenin-1 deficiency-report of three cases and review of the literature.Journal of inherited metabolic disease · 2017Article
- NHLRC1 repeat expansion in two beagles with Lafora disease.The Journal of small animal practice · 2016Article
- Lafora disease.Epileptic disorders : international epilepsy journal with videotape · 2016Review
- A novel mouse model that recapitulates adult-onset glycogenosis type 4.Human molecular genetics · 2015Article
- Article
- Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease.The Journal of biological chemistry · 2015Article
- Expression, purification and characterization of soluble red rooster laforin as a fusion protein in Escherichia coli.BMC biochemistry · 2014Article
- Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase.Molecular neurobiology · 2014Article
- Laforin prevents stress-induced polyglucosan body formation and Lafora disease progression in neurons.Molecular neurobiology · 2013Article
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Authors and funding
12 authors at 3 institutions in 2 countries.
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Abstract
The solubility of glycogen, essential to its metabolism, is a property of its shape, a sphere generated through extensive branching during synthesis. Lafora disease (LD) is a severe teenage-onset neurodegenerative epilepsy and results from multiorgan accumulations, termed Lafora bodies (LB), of abnormally structured aggregation-prone and digestion-resistant glycogen. LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively. The substrate and function of malin are unknown; an early counterintuitive observation in cell culture experiments that it targets laforin to proteasomal degradation was not pursued until now. The substrate and function of laforin have recently been elucidated. Laforin dephosphorylates glycogen during synthesis, without which phosphate ions interfere with and distort glycogen construction, leading to LB. We hypothesized that laforin in excess or not removed following its action on glycogen also interferes with glycogen formation. We show in malin-deficient mice that the absence of malin results in massively increased laforin preceding the appearance of LB and that laforin gradually accumulates in glycogen, which corresponds to progressive LB generation. We show that increasing the amounts of laforin in cell culture causes LB formation and that this occurs only with glycogen binding-competent laforin. In summary, malin deficiency causes increased laforin, increased laforin binding to glycogen, and LB formation. Furthermore, increased levels of laforin, when it can bind glycogen, causes LB. We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen.
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