Skip to main content
SpringerLink
Log in

Glycogen Metabolism and Lafora Disease

  • Chapter
  • First Online:
Protein Tyrosine Phosphatase Control of Metabolism

Abstract

Lafora disease is a juvenile-onset, fatal epilepsy that is characterized by the formation of Lafora bodies in many tissues, including skeletal muscle, heart, and neurons. Lafora bodies are insoluble deposits that contain polyglucosan, a poorly branched form of glycogen, and associated proteins. Evidence is mounting that Lafora bodies either cause or contribute to the pathology of the disease. It is a genetic disease caused by mutation in one of two genes, EPM2A and EPM2B, which encode, respectively, a phosphatase called laforin and an E3 ubiquitin ligase called malin. Laforin is a phosphatase of the atypical dual specificity phosphatase subfamily that, in vitro and in vivo, removes phosphate monoesters from glycogen. Normal glycogen contains trace amounts of phosphate introduced as a minor side reaction by the synthetic enzyme, glycogen synthase. In laforin knockout mice, glycogen becomes hyperphosphorylated and, as the mice age, acquires structural abnormalities and the tendency to come out of solution, consistent with Lafora body formation. Mutation of malin or laforin results in similar symptoms in patients and malin and laforin knockout mice exhibit phenotypic similarity in terms of neurological defects and abnormal glycogen metabolism, including hyperphosphorylation and Lafora body formation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AGL:

Glycogen debranching enzyme and gene

AMPK:

AMP-activated protein kinase

CBM:

Carbohydrate-binding module

GAA:

Lysosomal α-glucosidase and gene

GABARAP:

Gamma aminobutyric acid receptor-associated protein

GABARAPL1:

GABARAP-like 1

GL:

Product of PPP1R3B gene

GSD:

Glycogen storage disease

GSK-3:

Glycogen synthase kinase 3

mTOR:

Mammalian target of rapamycin

PAS:

Periodic acid-Schiff

PTEN:

Phosphatase and tensin homolog

PTG:

Protein targeting-to-glycogen product of the PPP1R3C gene

R6:

Product of the PPP1R3D gene

SEX4:

Starch excess 4

Stbd1:

Starch-binding domain-containing protein 1 also called genethonin 1

References

  1. Maehama T, Taylor GS, Dixon JE (2001) PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem 70:247–279

    Article  PubMed  CAS  Google Scholar 

  2. Lafora GR, Glueck B (1911) Beitrag zur histopathologie der myoklonischen epilepsie. Z Gesamte Neurol Psychiatr 6:1–14

    Article  Google Scholar 

  3. Gentry MS, Dixon JE, Worby CA (2009) Lafora disease: insights into neurodegeneration from plant metabolism. Trends Biochem Sci 34(12):628–639

    Article  PubMed  CAS  Google Scholar 

  4. Ganesh S, Puri R, Singh S, Mittal S, Dubey D (2006) Recent advances in the molecular basis of Lafora’s progressive myoclonus epilepsy. J Hum Genet 51(1):1–8

    Article  PubMed  CAS  Google Scholar 

  5. Delgado-Escueta AV (2007) Advances in Lafora progressive myoclonus epilepsy. Curr Neurol Neurosci Rep 7(5):428–433

    Article  PubMed  CAS  Google Scholar 

  6. Andrade DM, Turnbull J, Minassian BA (2007) Lafora disease, seizures and sugars. Acta Myol 26(1):83–86

    PubMed  CAS  Google Scholar 

  7. Ramachandran N, Girard JM, Turnbull J, Minassian BA (2009) The autosomal recessively inherited progressive myoclonus epilepsies and their genes. Epilepsia 50(suppl 5):29–36

    Article  PubMed  CAS  Google Scholar 

  8. Collins GH, Cowden RR, Nevis AH (1968) Myoclonus epilepsy with Lafora bodies. An ultrastructural and cytochemical study. Arch Pathol 86(3):239–254

    PubMed  CAS  Google Scholar 

  9. Ball S, Guan HP, James M, Myers A, Keeling P, Mouille G et al (1996) From glycogen to amylopectin: a model for the biogenesis of the plant starch granule. Cell 86(3):349–352

    Article  PubMed  CAS  Google Scholar 

  10. Zeeman SC, Smith SM, Smith AM (2007) The diurnal metabolism of leaf starch. Biochem J 401(1):13–28

    Article  PubMed  CAS  Google Scholar 

  11. Gentry MS, Roma-Mateo C, Sanz P (2012) Laforin, a protein with many faces: glucan phosphatase, adapter protein, and others. FEBS J 280(2):525–537

    Article  PubMed  CAS  Google Scholar 

  12. Roma-Mateo C, Sanz P, Gentry MS (2012) Deciphering the role of malin in the Lafora progressive myoclonus epilepsy. IUBMB Life 64(10):801–808

    Article  PubMed  CAS  Google Scholar 

  13. Roach PJ, Depaoli-Roach AA, Hurley TD, Tagliabracci VS (2012) Glycogen and its metabolism: some new developments and old themes. Biochem J 441(3):763–787

    Article  PubMed  CAS  Google Scholar 

  14. Roach PJ, Skurat AV (1997) Self-glucosylating initiator proteins and their role in glycogen biosynthesis. Prog Nucleic Acid Res Mol Biol 57:289–316

    Article  PubMed  CAS  Google Scholar 

  15. Smythe C, Cohen P (1991) The discovery of glycogenin and the priming mechanism for glycogen biogenesis. Eur J Biochem 200(3):625–631

    Article  PubMed  CAS  Google Scholar 

  16. Lomako J, Lomako WM, Whelan WJ (2004) Glycogenin: the primer for mammalian and yeast glycogen synthesis. Biochim Biophys Acta 1673(1–2):45–55

    Article  PubMed  CAS  Google Scholar 

  17. Hirschhorn R, Reuser AJ (2000) Glycogen storage disease type II: acid alpha-glucosidase (acid maltase) deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) He metabolic and molecular basis of inherited disease. McGraw-Hill, New York, pp 3389–3420

    Google Scholar 

  18. Yang Z, Klionsky DJ (2009) An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335:1–32

    Article  PubMed  CAS  Google Scholar 

  19. Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22(2):124–131

    Article  PubMed  CAS  Google Scholar 

  20. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y (2009) Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10(7):458–467

    Article  PubMed  CAS  Google Scholar 

  21. Rabinowitz JD, White E (2010) Autophagy and metabolism. Science 330(6009):1344–1348

    Article  PubMed  CAS  Google Scholar 

  22. Mizushima N, Yoshimori T, Ohsumi Y (2011) The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol 27:107–132

    Article  PubMed  CAS  Google Scholar 

  23. Raben N, Roberts A, Plotz PH (2007) Role of autophagy in the pathogenesis of Pompe disease. Acta Myol 26(1):45–48

    PubMed  CAS  Google Scholar 

  24. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7(3):279–296

    Article  PubMed  CAS  Google Scholar 

  25. Komatsu M, Ichimura Y (2010) Selective autophagy regulates various cellular functions. Genes Cells 15(9):923–933

    Article  PubMed  CAS  Google Scholar 

  26. Geng J, Klionsky DJ (2008) The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy. ‘Protein modifications: beyond the usual suspects’ review series. EMBO Rep 9(9):859–864

    Article  PubMed  CAS  Google Scholar 

  27. Noda NN, Ohsumi Y, Inagaki F (2010) Atg8-family interacting motif crucial for selective autophagy. FEBS Lett 584(7):1379–1385

    Article  PubMed  CAS  Google Scholar 

  28. Jiang S, Heller B, Tagliabracci VS, Zhai L, Irimia JM, DePaoli-Roach AA et al (2010) Starch binding domain-containing protein 1/genethonin 1 is a novel participant in glycogen metabolism. J Biol Chem 285(45):34960–34971

    Article  PubMed  CAS  Google Scholar 

  29. Christiansen C, Abou Hachem M, Janecek S, Vikso-Nielsen A, Blennow A, Svensson B (2009) The carbohydrate-binding module family 20—diversity, structure, and function. FEBS J 276(18):5006–5029

    Article  PubMed  CAS  Google Scholar 

  30. Jiang S, Wells CD, Roach PJ (2011) Starch-binding domain-containing protein 1 (Stbd1) and glycogen metabolism: identification of the Atg8 family interacting motif (AIM) in Stbd1 required for interaction with GABARAPL1. Biochem Biophys Res Commun 413(3):420–425

    Article  PubMed  CAS  Google Scholar 

  31. Chen Y-T, Burchell A (1995) Glycogen storage diseases. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York, pp 935–965

    Google Scholar 

  32. DiMauro S, Lamperti C (2001) Muscle glycogenoses. Muscle Nerve 24(8):984–999

    Article  PubMed  CAS  Google Scholar 

  33. DiMauro S, Spiegel R (2011) Progress and problems in muscle glycogenoses. Acta Myol 30(2):96–102

    PubMed  CAS  Google Scholar 

  34. Wilson WA, Wang Z, Roach PJ (2002) Systematic identification of the genes affecting glycogen storage in the yeast Saccharomyces cerevisiae: implication of the vacuole as a determinant of glycogen level. Mol Cell Proteomics 1(3):232–242

    Article  PubMed  CAS  Google Scholar 

  35. Andersen DH (1956) Familial cirrhosis of the liver with storage of abnormal glycogen. Lab Invest 5(1):11–20

    PubMed  CAS  Google Scholar 

  36. Moses SW, Parvari R (2002) The variable presentations of glycogen storage disease type IV: a review of clinical, enzymatic and molecular studies. Curr Mol Med 2(2):177–188

    Article  PubMed  CAS  Google Scholar 

  37. Nakajima H, Raben N, Hamaguchi T, Yamasaki T (2002) Phosphofructokinase deficiency; past, present and future. Curr Mol Med 2(2):197–212

    Article  PubMed  CAS  Google Scholar 

  38. McCue ME, Valberg SJ, Lucio M, Mickelson JR (2008) Glycogen synthase 1 (GYS1) mutation in diverse breeds with polysaccharide storage myopathy. J Vet Intern Med 22(5):1228–1233

    Article  PubMed  CAS  Google Scholar 

  39. Manchester J, Skurat AV, Roach P, Hauschka SD, Lawrence JC Jr (1996) Increased glycogen accumulation in transgenic mice overexpressing glycogen synthase in skeletal muscle. Proc Natl Acad Sci U S A 93(20):10707–10711

    Article  PubMed  CAS  Google Scholar 

  40. Pederson BA, Csitkovits AG, Simon R, Schroeder JM, Wang W, Skurat AV et al (2003) Overexpression of glycogen synthase in mouse muscle results in less branched glycogen. Biochem Biophys Res Commun 305(4):826–830

    Article  PubMed  CAS  Google Scholar 

  41. Raben N, Danon M, Lu N, Lee E, Shliselfeld L, Skurat AV et al (2001) Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 56(12):1739–1745

    Article  PubMed  CAS  Google Scholar 

  42. Pederson BA, Cope CR, Irimia JM, Schroeder JM, Thurberg BL, Depaoli-Roach AA et al (2005) Mice with elevated muscle glycogen stores do not have improved exercise performance. Biochem Biophys Res Commun 331(2):491–496

    Article  PubMed  CAS  Google Scholar 

  43. Minassian BA, Lee JR, Herbrick JA, Huizenga J, Soder S, Mungall AJ et al (1998) Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20(2):171–174

    Article  PubMed  CAS  Google Scholar 

  44. Serratosa JM, Gomez-Garre P, Gallardo ME, Anta B, de Bernabe DB, Lindhout D et al (1999) A novel protein tyrosine phosphatase gene is mutated in progressive myoclonus epilepsy of the Lafora type (EPM2). Hum Mol Genet 8(2):345–352

    Article  PubMed  CAS  Google Scholar 

  45. Chan EM, Young EJ, Ianzano L, Munteanu I, Zhao X, Christopoulos CC et al (2003) Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet 35(2):125–127

    Article  PubMed  CAS  Google Scholar 

  46. Garcia-Cabrero AM, Marinas A, Guerrero R, de Cordoba SR, Serratosa JM, Sanchez MP (2012) Laforin and malin deletions in mice produce similar neurologic impairments. J Neuropathol Exp Neurol 71(5):413–421

    Article  PubMed  CAS  Google Scholar 

  47. Gomez-Abad C, Gomez-Garre P, Gutierrez-Delicado E, Saygi S, Michelucci R, Tassinari CA et al (2005) Lafora disease due to EPM2B mutations: a clinical and genetic study. Neurology 64(6):982–986

    Article  PubMed  CAS  Google Scholar 

  48. Wang W, Lohi H, Skurat AV, DePaoli-Roach AA, Minassian BA, Roach PJ (2007) Glycogen metabolism in tissues from a mouse model of Lafora disease. Arch Biochem Biophys 457(2):264–269

    Article  PubMed  CAS  Google Scholar 

  49. Ceulemans H, Bollen M (2004) Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev 84(1):1–39

    Article  PubMed  CAS  Google Scholar 

  50. Wang J, Stuckey JA, Wishart MJ, Dixon JE (2002) A unique carbohydrate binding domain targets the Lafora disease phosphatase to glycogen. J Biol Chem 277(4):2377–2380

    Article  PubMed  CAS  Google Scholar 

  51. Wang W, Roach PJ (2004) Glycogen and related polysaccharides inhibit the laforin dual-specificity protein phosphatase. Biochem Biophys Res Commun 325(3):726–730

    Article  PubMed  CAS  Google Scholar 

  52. Chan EM, Ackerley CA, Lohi H, Ianzano L, Cortez MA, Shannon P et al (2004) Laforin preferentially binds the neurotoxic starch-like polyglucosans, which form in its absence in progressive myoclonus epilepsy. Hum Mol Genet 13(11):1117–1129

    Article  PubMed  CAS  Google Scholar 

  53. Ganesh S, Tsurutani N, Suzuki T, Hoshii Y, Ishihara T, Delgado-Escueta AV et al (2004) The carbohydrate-binding domain of Lafora disease protein targets Lafora polyglucosan bodies. Biochem Biophys Res Commun 313(4):1101–1109

    Article  PubMed  CAS  Google Scholar 

  54. Minassian BA, Ianzano L, Meloche M, Andermann E, Rouleau GA, Delgado-Escueta AV et al (2000) Mutation spectrum and predicted function of laforin in Lafora’s progressive myoclonus epilepsy. Neurology 55(3):341–346

    Article  PubMed  CAS  Google Scholar 

  55. Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A et al (2004) Protein tyrosine phosphatases in the human genome. Cell 117(6):699–711

    Article  PubMed  CAS  Google Scholar 

  56. Ganesh S, Agarwala KL, Ueda K, Akagi T, Shoda K, Usui T et al (2000) Laforin, defective in the progressive myoclonus epilepsy of Lafora type, is a dual-specificity phosphatase associated with polyribosomes. Hum Mol Genet 9(15):2251–2261

    Article  PubMed  CAS  Google Scholar 

  57. Lohi H, Ianzano L, Zhao XC, Chan EM, Turnbull J, Scherer SW et al (2005) Novel glycogen synthase kinase 3 and ubiquitination pathways in progressive myoclonus epilepsy. Hum Mol Genet 14(18):2727–2736

    Article  PubMed  CAS  Google Scholar 

  58. Wang Y, Liu Y, Wu C, Zhang H, Zheng X, Zheng Z et al (2006) Epm2a suppresses tumor growth in an immunocompromised host by inhibiting Wnt signaling. Cancer Cell 10(3):179–190

    Article  PubMed  CAS  Google Scholar 

  59. Worby CA, Gentry MS, Dixon JE (2006) Laforin: a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem 281:30412–30418

    Article  PubMed  CAS  Google Scholar 

  60. Tagliabracci VS, Turnbull J, Wang W, Girard JM, Zhao X, Skurat AV et al (2007) Laforin is a glycogen phosphatase, deficiency of which leads to elevated phosphorylation of glycogen in vivo. Proc Natl Acad Sci U S A 104(49):19262–19266

    Article  PubMed  CAS  Google Scholar 

  61. Blennow A, Nielsen TH, Baunsgaard L, Mikkelsen R, Engelsen SB (2002) Starch phosphorylation: a new front line in starch research. Trends Plant Sci 7(10):445–450

    Article  PubMed  CAS  Google Scholar 

  62. Fontana JD (1980) The presence of phosphate in glycogen. FEBS Lett 109(1):85–92

    Article  PubMed  CAS  Google Scholar 

  63. Lomako J, Lomako WM, Kirkman BR, Whelan WJ (1994) The role of phosphate in muscle glycogen. Biofactors 4(3–4):167–171

    PubMed  CAS  Google Scholar 

  64. Tagliabracci VS, Heiss C, Karthik C, Contreras CJ, Glushka J, Ishihara M et al (2011) Phosphate incorporation during glycogen synthesis and Lafora disease. Cell Metab 13(3):274–282

    Article  PubMed  CAS  Google Scholar 

  65. Tagliabracci VS, Girard JM, Segvich D, Meyer C, Turnbull J, Zhao X et al (2008) Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem 283(49):33816–33825

    Article  PubMed  CAS  Google Scholar 

  66. Hejazi M, Fettke J, Kotting O, Zeeman SC, Steup M (2010) The laforin-like dual-specificity phosphatase SEX4 from arabidopsis hydrolyzes both C6- and C3-phosphate esters introduced by starch-related dikinases and thereby affects phase transition of alpha-glucans. Plant Physiol 152(2):711–722

    Article  PubMed  CAS  Google Scholar 

  67. Niittyla T, Comparot-Moss S, Lue WL, Messerli G, Trevisan M, Seymour MD et al (2006) Similar protein phosphatases control starch metabolism in plants and glycogen metabolism in mammals. J Biol Chem 281(17):11815–11818

    Article  PubMed  CAS  Google Scholar 

  68. Gessler K, Uson I, Takaha T, Krauss N, Smith SM, Okada S et al (1999) V-amylose at atomic resolution: X-ray structure of a cycloamylose with 26 glucose residues (cyclomaltohexaicosaose). Proc Natl Acad Sci U S A 96(8):4246–4251

    Article  PubMed  CAS  Google Scholar 

  69. Ritte G, Heydenreich M, Mahlow S, Haebel S, Kotting O, Steup M (2006) Phosphorylation of C6- and C3-positions of glucosyl residues in starch is catalysed by distinct dikinases. FEBS Lett 580(20):4872–4876

    Article  PubMed  CAS  Google Scholar 

  70. Fettke J, Hejazi M, Smirnova J, Hochel E, Stage M, Steup M (2009) Eukaryotic starch degradation: integration of plastidial and cytosolic pathways. J Exp Bot 60(10):2907–2922

    Article  PubMed  CAS  Google Scholar 

  71. Roach PJ (2011) Are there errors in glycogen biosynthesis and is laforin a repair enzyme? FEBS Lett 585(20):3216–3218

    Article  PubMed  CAS  Google Scholar 

  72. Machado-Salas J, Avila-Costa MR, Guevara P, Guevara J, Duron RM, Bai D et al (2012) Ontogeny of Lafora bodies and neurocytoskeleton changes in laforin-deficient mice. Exp Neurol 236(1):131–140

    Article  PubMed  CAS  Google Scholar 

  73. Ganesh S, Delgado-Escueta AV, Sakamoto T, Avila MR, Machado-Salas J, Hoshii Y et al (2002) Targeted disruption of the Epm2a gene causes formation of Lafora inclusion bodies, neurodegeneration, ataxia, myoclonus epilepsy and impaired behavioral response in mice. Hum Mol Genet 11(11):1251–1262

    Article  PubMed  CAS  Google Scholar 

  74. Duran J, Tevy MF, Garcia-Rocha M, Calbo J, Milan M, Guinovart JJ (2012) Deleterious effects of neuronal accumulation of glycogen in flies and mice. EMBO Mol Med 4(8): 719–729

    Article  PubMed  CAS  Google Scholar 

  75. Zhai L, Choi CS, Irimia-Dominguez J, McGuire AC, Kim S, Bock CB et al (2007) Enhanced insulin sensitivity and energy expenditure in PPP1R3C (PTG) deleted mice. Diabetes 56(1):A62

    Google Scholar 

  76. Turnbull J, DePaoli-Roach AA, Zhao X, Cortez MA, Pencea N, Tiberia E et al (2011) PTG depletion removes Lafora bodies and rescues the fatal epilepsy of Lafora disease. PLoS Genet 7(4):e1002037

    Article  PubMed  CAS  Google Scholar 

  77. Guerrero R, Vernia S, Sanz R, Abreu-Rodriguez I, Almaraz C, Garcia-Hoyos M et al (2011) A PTG variant contributes to a milder phenotype in Lafora disease. PLoS One 6(6):e21294

    Article  PubMed  CAS  Google Scholar 

  78. Khersonsky O, Tawfik DS (2010) Enzyme promiscuity: a mechanistic and evolutionary perspective. Annu Rev Biochem 79:471–505

    Article  PubMed  CAS  Google Scholar 

  79. Bollen M, Peti W, Ragusa MJ, Beullens M (2010) The extended PP1 toolkit: designed to create specificity. Trends Biochem Sci 35(8):450–458

    Article  PubMed  CAS  Google Scholar 

  80. Vernia S, Heredia M, Criado O, Rodriguez de Cordoba S, Garcia-Roves PM, Cansell C et al (2011) Laforin, a dual specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice. Hum Mol Genet 20:2571–2584

    Article  PubMed  CAS  Google Scholar 

  81. DePaoli-Roach AA, Segvich DM, Meyer CM, Rahimi Y, Worby CA, Gentry MS et al (2012) Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity. Hum Mol Genet 21(7):1604–1610

    Article  PubMed  CAS  Google Scholar 

  82. Gentry MS, Worby CA, Dixon JE (2005) Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin. Proc Natl Acad Sci U S A 102(24):8501–8506

    Article  PubMed  CAS  Google Scholar 

  83. Roma-Mateo C, Solaz-Fuster Mdel C, Gimeno-Alcaniz JV, Dukhande VV, Donderis J, Worby CA et al (2011) Laforin, a dual-specificity phosphatase involved in Lafora disease, is phosphorylated at Ser25 by AMP-activated protein kinase. Biochem J 439(2):265–275

    Article  PubMed  CAS  Google Scholar 

  84. Solaz-Fuster MC, Gimeno-Alcaniz JV, Ros S, Fernandez-Sanchez ME, Garcia-Fojeda B, Criado Garcia O et al (2008) Regulation of glycogen synthesis by the laforin-malin complex is modulated by the AMP-activated protein kinase pathway. Hum Mol Genet 17(5):667–678

    Article  PubMed  CAS  Google Scholar 

  85. DePaoli-Roach AA, Tagliabracci VS, Segvich DM, Meyer CM, Irimia JM, Roach PJ (2010) Genetic depletion of the malin E3 ubiquitin ligase in mice leads to Lafora bodies and the accumulation of insoluble laforin. J Biol Chem 285(33):25372–25381

    Article  PubMed  CAS  Google Scholar 

  86. Moreno D, Towler MC, Hardie DG, Knecht E, Sanz P (2010) The laforin-malin complex, involved in Lafora disease, promotes the incorporation of K63-linked ubiquitin chains into AMP-activated protein kinase beta subunits. Mol Biol Cell 21(15):2578–2588

    Article  PubMed  CAS  Google Scholar 

  87. Sharma J, Mulherkar S, Mukherjee D, Jana NR (2012) Malin regulates Wnt signaling pathway through degradation of dishevelled2. J Biol Chem 287(9):6830–6839

    Article  PubMed  CAS  Google Scholar 

  88. Vilchez D, Ros S, Cifuentes D, Pujadas L, Valles J, Garcia-Fojeda B et al (2007) Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10(11):1407–1413

    Article  PubMed  CAS  Google Scholar 

  89. Worby CA, Gentry MS, Dixon JE (2008) Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem 283(7):4069–4076

    Article  PubMed  CAS  Google Scholar 

  90. Cheng A, Zhang M, Gentry MS, Worby CA, Dixon JE, Saltiel AR (2007) A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori’s disease. Genes Dev 21(19):2399–2409

    Article  PubMed  CAS  Google Scholar 

  91. Sharma J, Rao SN, Shankar SK, Satishchandra P, Jana NR (2011) Lafora disease ubiquitin ligase malin promotes proteasomal degradation of neuronatin and regulates glycogen synthesis. Neurobiol Dis 44(1):133–141

    Article  PubMed  CAS  Google Scholar 

  92. Turnbull J, Wang P, Girard JM, Ruggieri A, Wang TJ, Draginov AG et al (2010) Glycogen hyperphosphorylation underlies Lafora body formation. Ann Neurol 68(6):925–933

    Article  PubMed  CAS  Google Scholar 

  93. Valles-Ortega J, Duran J, Garcia-Rocha M, Bosch C, Saez I, Pujadas L et al (2011) Neurodegeneration and functional impairments associated with glycogen synthase accumulation in a mouse model of Lafora disease. EMBO Mol Med 3(11):667–681

    Article  PubMed  CAS  Google Scholar 

  94. Criado O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM, Vernia S et al (2012) Lafora bodies and neurological defects in malin-deficient mice correlate with impaired autophagy. Hum Mol Genet 21(7):1521–1533

    Article  PubMed  CAS  Google Scholar 

  95. Tiberia E, Turnbull J, Wang T, Ruggieri A, Zhao XC, Pencea N et al (2012) Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease. J Biol Chem 287(30):25650–25659

    Article  PubMed  CAS  Google Scholar 

  96. Suzuki Y, Lanner C, Kim JH, Vilardo PG, Zhang H, Yang J et al (2001) Insulin control of glycogen metabolism in knockout mice lacking the muscle-specific protein phosphatase PP1G/RGL. Mol Cell Biol 21(8):2683–2694

    Article  PubMed  CAS  Google Scholar 

  97. Wang Z, Wilson WA, Fujino MA, Roach PJ (2001) Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol Cell Biol 21(17):5742–5752

    Article  PubMed  CAS  Google Scholar 

  98. Aguado C, Sarkar S, Korolchuk VI, Criado O, Vernia S, Boya P et al (2010) Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet 19(14):2867–2876

    Article  PubMed  CAS  Google Scholar 

  99. Puri R, Suzuki T, Yamakawa K, Ganesh S (2012) Dysfunctions in endosomal-lysosomal and autophagy pathways underlie neuropathology in a mouse model for Lafora disease. Hum Mol Genet 21(1):175–184

    Article  PubMed  CAS  Google Scholar 

  100. Knecht E, Criado-Garcia O, Aguado C, Gayarre J, Duran-Trio L, Garcia-Cabrero AM et al (2012) Malin knockout mice support a primary role of autophagy in the pathogenesis of Lafora disease. Autophagy 8(4):701–703

    Article  PubMed  CAS  Google Scholar 

  101. Puri R, Ganesh S (2012) Autophagy defects in Lafora disease: cause or consequence? Autophagy 8(2):289–290

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Research from the authors’ laboratories was supported by NIH grants R37 DK27221, R01 NS056454, and R21 HL108301.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA

    Peter J. Roach Ph.D. & Anna A. DePaoli-Roach Ph.D.

Authors
  1. Peter J. Roach Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anna A. DePaoli-Roach Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter J. Roach Ph.D. .

Editor information

Editors and Affiliations

  1. Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Kendra K. Bence

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Roach, P.J., DePaoli-Roach, A.A. (2013). Glycogen Metabolism and Lafora Disease. In: Bence, K. (eds) Protein Tyrosine Phosphatase Control of Metabolism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7855-3_13

Download citation

Publish with us

Policies and ethics

Search

Navigation