PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease
Lafora disease is the most common teenage-onset neurodegenerative disease, the main teenage-onset form of progressive myoclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. Polyglucosan formation is catalyzed by glycogen synthase, which is activated through dephosphorylation by glycogen-associated protein phosphatase-1 (PP1). Here we remove PTG, one of the proteins that target PP1 to glycogen, from mice with Lafora disease. This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases.
Vyšlo v časopise:
PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease. PLoS Genet 7(4): e32767. doi:10.1371/journal.pgen.1002037
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002037
Souhrn
Lafora disease is the most common teenage-onset neurodegenerative disease, the main teenage-onset form of progressive myoclonus epilepsy (PME), and one of the severest epilepsies. Pathologically, a starch-like compound, polyglucosan, accumulates in neuronal cell bodies and overtakes neuronal small processes, mainly dendrites. Polyglucosan formation is catalyzed by glycogen synthase, which is activated through dephosphorylation by glycogen-associated protein phosphatase-1 (PP1). Here we remove PTG, one of the proteins that target PP1 to glycogen, from mice with Lafora disease. This results in near-complete disappearance of polyglucosans and in resolution of neurodegeneration and myoclonic epilepsy. This work discloses an entryway to treating this fatal epilepsy and potentially other glycogen storage diseases.
Zdroje
1. ChanEMYoungEJIanzanoLMunteanuIZhaoX 2003 Mutations in NHLRC1 cause progressive myoclonus epilepsy. Nat Genet 35 125 127
2. MinassianBALeeJRHerbrickJAHuizengaJSoderS 1998 Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonus epilepsy. Nat Genet 20 171 174
3. CavanaghJB 1999 Corpora-amylacea and the family of polyglucosan diseases. Brain Res Brain Res Rev 29 265 295
4. LaforaGRGlueckB 1911 Beitrag zur Histopathologie der myoklonischen Epilepsie. Zeitschrift Gesamte Neurologische Psychiatrie 6 1 14
5. MinassianBA 2001 Lafora's disease: towards a clinical, pathologic, and molecular synthesis. Pediatr Neurol 25 21 29
6. Van Heycop Ten HamM 1975 Lafora disease, a form of progressive myoclonus epilepsy. VinkenPJBG The epilepsies; Handbook of clinical neurology Amsterdam Elsevier 382 422
7. GrahamTEYuanZHillAKWilsonRJ 2010 The regulation of muscle glycogen: the granule and its proteins. Acta Physiol (Oxf) 199 489 498
8. HejaziMFettkeJHaebelSEdnerCParisO 2008 Glucan, water dikinase phosphorylates crystalline maltodextrins and thereby initiates solubilization. Plant J 55 323 334
9. SakaiMAustinJWitmerFTruebL 1970 Studies in myoclonus epilepsy (Lafora body form). II. Polyglucosans in the systemic deposits of myoclonus epilepsy and in corpora amylacea. Neurology 20 160 176
10. FongNMJensenTCShahASParekhNNSaltielAR 2000 Identification of binding sites on protein targeting to glycogen for enzymes of glycogen metabolism. J Biol Chem 275 35034 35039
11. PrintenJABradyMJSaltielAR 1997 PTG, a protein phosphatase 1-binding protein with a role in glycogen metabolism. Science 275 1475 1478
12. Fernandez-SanchezMECriado-GarciaOHeathKEGarcia-FojedaBMedrano-FernandezI 2003 Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. Hum Mol Genet 12 3161 3171
13. VilchezDRosSCifuentesDPujadasLVallesJ 2007 Mechanism suppressing glycogen synthesis in neurons and its demise in progressive myoclonus epilepsy. Nat Neurosci 10 1407 1413
14. WorbyCAGentryMSDixonJE 2008 Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG). J Biol Chem 283 4069 4076
15. DePaoli-RoachAATagliabracciVSSegvichDMMeyerCMIrimiaJM 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 25372 25381
16. TagliabracciVSGirardJMSegvichDMeyerCTurnbullJ 2008 Abnormal metabolism of glycogen phosphate as a cause for Lafora disease. J Biol Chem 283 33816 33825
17. TurnbullJWangPXGirardJMRuggieriAWangTJ 2010 Glycogen hyperphosphorylation underlies Lafora Body formation. Ann Neurol Epub Oct 28
18. TagliabracciVSTurnbullJWangWGirardJMZhaoX 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 19262 19266
19. WorbyCAGentryMSDixonJE 2006 Laforin, a dual specificity phosphatase that dephosphorylates complex carbohydrates. J Biol Chem 281 30412 30418
20. PedersonBACopeCRSchroederJMSmithMWIrimiaJM 2005 Exercise capacity of mice genetically lacking muscle glycogen synthase: in mice, muscle glycogen is not essential for exercise. J Biol Chem 280 17260 17265
21. PedersonBAChenHSchroederJMShouWDePaoli-RoachAA 2004 Abnormal cardiac development in the absence of heart glycogen. Mol Cell Biol 24 7179 7187
22. CrossonSMKhanAPrintenJPessinJESaltielAR 2003 PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. J Clin Invest 111 1423 1432
23. ZhaiLChoiCSIrimia-DominguezJMcguireACKimS 2007 Enhanced Insulin Sensitivity and Energy Expenditure in PPP1R3C (PTG) Deleted Mice. Diabetes 56 A62
24. GaneshSDelgado-EscuetaAVSakamotoTAvilaMRMachado-SalasJ 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 1251 1262
25. CromptonDEBerkovicSF 2009 The borderland of epilepsy: clinical and molecular features of phenomena that mimic epileptic seizures. Lancet Neurol 8 370 381
26. YokoiFDangMTLiJLiY 2006 Myoclonus, motor deficits, alterations in emotional responses and monoamine metabolism in epsilon-sarcoglycan deficient mice. J Biochem 140 141 146
27. LohiHYoungEJFitzmauriceSNRusbridgeCChanEM 2005 Expanded repeat in canine epilepsy. Science 307 81
28. CeulemansHBollenM 2004 Functional diversity of protein phosphatase-1, a cellular economizer and reset button. Physiol Rev 84 1 39
29. YokoiSAustinJWitmerFSakaiM 1968 Studies in myoclonus epilepsy (Lafora body form). I. Isolation and preliminary characterization of Lafora bodies in two cases. Arch Neurol 19 15 33
30. GaryaliPSiwachPSinghPKPuriRMittalS 2009 The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system. Hum Mol Genet 18 688 700
31. RaoSNMaityRSharmaJDeyPShankarSK 2010 Sequestration of chaperones and proteasome into Lafora bodies and proteasomal dysfunction induced by Lafora disease-associated mutations of malin. Hum Mol Genet 19 4726 4734
32. VerniaSRubioTHerediaMRodriguez de CordobaSSanzP 2009 Increased endoplasmic reticulum stress and decreased proteasomal function in lafora disease models lacking the phosphatase laforin. PLoS One 4 e5907 doi:10.1371/journal.pone.0005907
33. AguadoCSarkarSKorolchukVICriadoOVerniaS 2010 Laforin, the most common protein mutated in Lafora disease, regulates autophagy. Hum Mol Genet 19 2867 2876
34. LossosAMeinerZBarashVSofferDSchlesingerI 1998 Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene. Ann Neurol 44 867 872
35. RobitailleYCarpenterSKarpatiGDiMauroSD 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 103 315 336
36. KelkerMSPageRPetiW 2009 Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors. J Mol Biol 385 11 21
37. BaskaranSRoachPJDePaoli-RoachAAHurleyTD 2010 Structural basis for glucose-6-phosphate activation of glycogen synthase. Proc Natl Acad Sci U S A 107 17563 17568
38. HorcajadaCGuinovartJJFitaIFerrerJC 2006 Crystal structure of an archaeal glycogen synthase: insights into oligomerization and substrate binding of eukaryotic glycogen synthases. J Biol Chem 281 2923 2931
39. BarfordDJohnsonLN 1989 The allosteric transition of glycogen phosphorylase. Nature 340 609 616
40. GoldsmithEJSprangSRHamlinRXuongNHFletterickRJ 1989 Domain separation in the activation of glycogen phosphorylase a. Science 245 528 532
41. LoweEDNobleMESkamnakiVTOikonomakosNGOwenDJ 1997 The crystal structure of a phosphorylase kinase peptide substrate complex: kinase substrate recognition. EMBO J 16 6646 6658
42. BrunoCvan DiggelenOPCassandriniDGimpelevMGiuffreB 2004 Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 63 1053 1058
43. van der PloegATReuserAJ 2008 Pompe's disease. Lancet 372 1342 1353
44. Douillard-GuillouxGRabenNTakikitaSFerryAVignaudA 2010 Restoration of muscle functionality by genetic suppression of glycogen synthesis in a murine model of Pompe disease. Hum Mol Genet 19 684 696
45. KollbergGTuliniusMGilljamTOstman-SmithIForsanderG 2007 Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0. N Engl J Med 357 1507 1514
46. WeibelER 1979 Point counting methods. WeibelER Stereological Methods, Practical Methods for Biological Morphometry London Academic Press 101 159
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 4
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- PTG Depletion Removes Lafora Bodies and Rescues the Fatal Epilepsy of Lafora Disease
- Survival Motor Neuron Protein Regulates Stem Cell Division, Proliferation, and Differentiation in
- An Evolutionary Genomic Approach to Identify Genes Involved in Human Birth Timing
- Loss-of-Function Mutations in Cause Metachondromatosis, but Not Ollier Disease or Maffucci Syndrome