Lafora disease, seizures and sugars.

Division of Neurology, Krembil Neuroscience Centre, University of Toronto, Toronto Western Hospital, Toronto, Canada.
Acta myologica: myopathies and cardiomyopathies: official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases 08/2007; 26(1):83-6.
Source: PubMed

ABSTRACT Lafora disease (LD) is the most severe form of Progressive Myoclonus Epilepsy with teenage onset. It has an autosomal recessive mode of inheritance and is almost universally fatal by the second or third decade of life. To date, there is no prevention or cure. In the last decade, with the identification of the genes responsible for this disease, much knowledge has been gained with the potential for the future development of effective treatment. This review will briefly address clinical issues and will focus on the molecular aspects of the disease.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Glycogen is a branched polymer of glucose that acts as an energy reserve in many cell types. Glycogen contains trace amounts of covalent phosphate, in the range of one phosphate per 500-2000 glucose residues, depending on the source. The function, if any, is unknown but in at least one genetic disease, the progressive myooclonic epilepsy Lafora disease, excessive phosphorylation of glycogen has been implicated in the pathology by disturbing glycogen structure. Some 90% of Lafora cases are attributed to mutations of the EPM2A or EPM2B genes and mice with either gene disrupted accumulate hyperphosphorylated glycogen. It is therefore of importance to understand the chemistry of glycogen phosphorylation. Rabbit skeletal muscle glycogen contained covalent phosphate as monoesters of C2, C3 and C6 carbons of glucose residues based on analyses of phospho-oligosaccharides by NMR. Furthermore, using a sensitive assay for glucose-6-P in hydrolysates of glycogen coupled with measurement of total phosphate, we determined the proportion of C6 phosphorylation in rabbit muscle glycogen to be ~20%. C6 phosphorylation also accounted for ~20% of the covalent phosphate in wild type mouse muscle glycogen. Glycogen phosphorylation in Epm2a-/- and Epm2b-/- mice was increased eight- and four-fold compared to wild type mice but the proportion of C6 phosphorylation remained unchanged at ~20%. Therefore, our results suggest that C2, C3 and/or C6 phosphate could all contribute to abnormal glycogen structure or to Lafora disease. Copyright © 2014, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 11/2014; 290(2). DOI:10.1074/jbc.M114.607796 · 4.60 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Uncontrolled elongation of glycogen chains, not adequately balanced by their branching, leads to the formation of an insoluble, presumably neurotoxic, form of glycogen called polyglucosan. To test the suspected pathogenicity of polyglucosans in neurological glycogenoses, we have modeled the typical glycogenosis Adult Polyglucosan Body Disease (APBD) by suppressing glycogen branching enzyme 1 (GBE1, EC expression using lentiviruses harboring short hairpin RNA (shRNA). GBE1 suppression in embryonic cortical neurons led to polyglucosan accumulation and associated apoptosis, which were reversible by rapamycin or starvation treatments. Further analysis revealed that rapamycin and starvation led to phosphorylation and inactivation of glycogen synthase (GS, EC, dephosphorylated and activated in the GBE1-suppressed neurons. These protective effects of rapamycin and starvation were reversed by overexpression of phosphorylation-site mutant GS only if its glycogen binding site was intact. While rapamycin and starvation induce autophagy, autophagic maturation was not required for their corrective effects, which prevailed even if autophagic flux was inhibited by vinblastine. Furthermore, polyglucosans were not observed in any compartment along the autophagic pathway. Our data suggest that GBE repression in glycogenoses can cause pathogenic polyglucosan buildup, which might be corrected by GS inhibition. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 04/2013; 127(1). DOI:10.1111/jnc.12277 · 4.24 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Glycogen is a glucose polymer that contains minor amounts of covalently attached phosphate. Hyperphosphorylation is deleterious to glycogen structure and can lead to Lafora disease. Recently, it was demonstrated that glycogen synthase catalyzes glucose-phosphate transfer in addition to its characteristic glucose transfer reaction. Glucose-1,2-cyclic-phosphate (GCP) was proposed to be formed from UDP-Glc breakdown and subsequently transferred, thus providing a source of phosphate found in glycogen. To gain further insight into the molecular basis for glucose-phosphate transfer, two structures of yeast glycogen synthase were determined; a 3.0-Å resolution structure of the complex with UMP/GCP and a 2.8-Å resolution structure of the complex with UDP/glucose. Structural superposition of the complexes revealed that the bound ligands and most active site residues are positioned similarly, consistent with the use of a common transfer mechanism for both reactions. The N-terminal domain of the UDP⋅glucose complex was found to be 13.3° more closed compared with a UDP complex. However, the UMP⋅GCP complex was 4.8° less closed than the glucose complex, which may explain the low efficiency of GCP transfer. Modeling of either α- or β-glucose or a mixture of both anomers can account for the observed electron density of the UDP⋅glucose complex. NMR studies of UDP-Glc hydrolysis by yeast glycogen synthase were used to verify the stereochemistry of the product, and they also showed synchronous GCP accumulation. The similarities in the active sites of glycogen synthase and glycogen phosphorylase support the idea of a common catalytic mechanism in GT-B enzymes independent of the specific reaction catalyzed.
    Proceedings of the National Academy of Sciences 12/2013; DOI:10.1073/pnas.1310106111 · 9.81 Impact Factor

Full-text (2 Sources)

Available from
May 30, 2014