Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?
- 392 Downloads
Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K+ by astrocytes, thereby leading to increased extracellular K+ and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K+ homeostasis and increased susceptibility to seizures in epilepsy.
KeywordsAstrocytes Glycogen Potassium Glutamate Epilepsy
Glycogen synthase kinase 3
Non rapid eye movement
Vasoactive intestinal peptide
The author S.M. thanks the grant KL2 RR033182 from the National Insititute of Health (NIH) to the University of Minnesota Clinical and Translational Science Institute (CTSI) for support.
Disclosure/Conflict of interests
The authors declare no conflict of interest.
- Boison D (2011) Methylxanthines, seizures, and excitotoxicity. Handb Exp Pharmacol 200:251–266Google Scholar
- Choi HB, Gordon GR, Zhou N, Tai C, Rungta RL, Martinez J, Milner TA, Ryu JK, McLarnon JG, Tresguerres M, Levin LR, Buck J, MacVicar BA (2012) Metabolic communication between astrocytes and neurons via bicarbonate-responsive soluble adenylyl cyclase. Neuron 75:1094–1104PubMedCentralPubMedGoogle Scholar
- Cloix JF, Hevor T (2011) Glycogen as a putative target for diagnosis and therapy in brain pathologies. ISRN Pathology. doi: 10.5402/2011/930729
- Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S, San Millan B, Heredia M, Roma-Mateo C, Mouron S, Juana-Lopez L, Dominguez M, Navarro C, Serratosa JM, Sanchez M, Sanz P, Bovolenta P, Knecht E, Rodriguez de Cordoba S (2012) Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet 21:1521–1533PubMedGoogle Scholar
- Duran J, Gruart A, Garcia-Rocha M, Delgado-Garcia JM, Guinovart JJ (2014) Glycogen accumulation underlies neurodegeneration and autophagy impairment in Lafora disease. Hum Mol Genet. doi: 10.1093/hmg/ddu024
- Eid T, Thomas MJ, Spencer DD, Runden-Pran E, Lai JC, Malthankar GV, Kim JH, Danbolt NC, Ottersen OP, de Lanerolle NC (2004) Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Lancet 363:28–37PubMedGoogle Scholar
- Konnerth A, Heinemann U, Yaari Y (1986) Nonsynaptic epileptogenesis in the mammalian hippocampus in vitro. I Development of seizurelike activity in low extracellular calcium J Neurophysiol 56:409–423Google Scholar
- Liu Y, Zeng L, Ma K, Baba O, Zheng P, Liu Y, Wang Y (2013) Laforin-Malin Complex Degrades Polyglucosan Bodies in Concert with Glycogen Debranching Enzyme and Brain Isoform Glycogen Phosphorylase. Mol Neurobiol 49:645–657Google Scholar
- McKenna MC (2013) Glutamate Pays Its Own Way in Astrocytes. Front Endocrinol (Lausanne) 4:191Google Scholar
- Nitschke F, Wang P, Schmieder P, Girard JM, Awrey DE, Wang T, Israelian J, Zhao X, Turnbull J, Heydenreich M, Kleinpeter E, Steup M, Minassian BA (2013) Hyperphosphorylation of glucosyl C6 carbons and altered structure of glycogen in the neurodegenerative epilepsy Lafora disease. Cell Metab 17:756–767PubMedGoogle Scholar
- Robitaille Y, Carpenter S, Karpati G, DiMauro SD (1980) A distinct form of adult polyglucosan body disease with massive involvement of central and peripheral neuronal processes and astrocytes: a report of four cases and a review of the occurrence of polyglucosan bodies in other conditions such as Lafora’s disease and normal ageing. Brain 103:315–336PubMedGoogle Scholar
- Sonnewald U, Westergaard N, Petersen SB, Unsgard G, Schousboe A (1993) Metabolism of [U-13C]glutamate in astrocytes studied by 13C NMR spectroscopy: incorporation of more label into lactate than into glutamine demonstrates the importance of the tricarboxylic acid cycle. J Neurochem 61:1179–1182PubMedGoogle Scholar
- Valles-Ortega J, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L, Serafin A, Canas X, Soriano E, Delgado-Garcia JM, Gruart A, Guinovart JJ (2011) Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Mol Med 3:667–681PubMedCentralPubMedGoogle Scholar
- Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B, Criado-Garcia O, Fernandez-Sanchez E, Medrano-Fernandez I, Dominguez J, Garcia-Rocha M, Soriano E, Rodriguez de Cordoba S, Guinovart JJ (2007) Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10:1407–1413PubMedGoogle Scholar