Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease

English version České info

Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5–6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.

Vyšlo v časopise: Fatal Prion Disease in a Mouse Model of Genetic E200K Creutzfeldt-Jakob Disease. PLoS Pathog 7(11): e32767. doi:10.1371/journal.ppat.1002350
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002350

Souhrn

Zdroje

1. KovacsGGPuopoloMLadoganaAPocchiariMBudkaH 2005 Genetic prion disease: the EUROCJD experience. Hum Genet 118 166 174

2. HsiaoKPrusinerSB 1990 Inherited human prion diseases. Neurology 40 1820 1827

3. HsiaoKMeinerZKahanaECassCKahanaI 1991 Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N Engl J Med 324 1091 1097

4. KorczynADChapmanJGoldfarbLGBrownPGajdusekDC 1991 A mutation in the prion protein gene in Creutzfeldt-Jakob disease in Jewish patients of Libyan, Greek, and Tunisian origin. Ann N Y Acad Sci 640 171 176

5. LeeHSSambuughinNCervenakovaLChapmanJPocchiariM 1999 Ancestral origins and worldwide distribution of the PRNP 200K mutation causing familial Creutzfeldt-Jakob disease. Am J Hum Genet 64 1063 1070

6. StewartLARydzewskaLHKeoghGFKnightRS 2008 Systematic review of therapeutic interventions in human prion disease. Neurology 70 1272 1281

7. GeschwindMD 2009 Clinical trials for prion disease: difficult challenges, but hope for the future. Lancet Neurol 8 304 306

8. OttoMCepekLRatzkaPDoehlingerSBoekhoffI 2004 Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study. Neurology 62 714 718

9. BrownPGibbsCJJrRodgers-JohnsonPAsherDMSulimaMP 1994 Human spongiform encephalopathy: the National Institutes of Health series of 300 cases of experimentally transmitted disease. Ann Neurol 35 513 529

10. TateishiJKitamotoT 1995 Inherited prion diseases and transmission to rodents. Brain Pathol 5 53 59

11. GroschupMHBuschmannA 2008 Rodent models for prion diseases. Vet Res 39 32

12. SolomonIHSchepkerJAHarrisDA 2010 Prion neurotoxicity: insights from prion protein mutants. Curr Issues Mol Biol 12 51 61

13. HsiaoKKScottMFosterDGrothDFDeArmondSJ 1990 Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250 1587 1590

14. HsiaoKKGrothDScottMYangSLSerbanH 1994 Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci U S A 91 9126 9130

15. TellingGCScottMHsiaoKKFosterDYangSL 1994 Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci U S A 91 9936 9940

16. ChiesaRPiccardoPGhettiBHarrisDA 1998 Neurological illness in transgenic mice expressing a prion protein with an insertional mutation. Neuron 21 1339 1351

17. YangWCookJRassbachBLemusADeArmondSJ 2009 A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP. J Neurosci 29 10072 10080

18. DossenaSImeriLMangieriMGarofoliAFerrariL 2008 Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model. Neuron 60 598 609

19. JacksonWSBorkowskiAWFaasHSteeleADKingOD 2009 Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice. Neuron 63 438 450

20. AsanteEAGowlandIGrimshawALinehanJMSmidakM 2009 Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins. J Gen Virol 90 546 558

21. TellingGCHagaTTorchiaMTremblayPDeArmondSJ 1996 Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes Dev 10 1736 1750

22. ScottMRKohlerRFosterDPrusinerSB 1992 Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci 1 986 997

23. KovacsGGBudkaH 2009 Molecular pathology of human prion diseases. Int J Mol Sci 10 976 999

24. KovacsGGSeguinJQuadrioIHoftbergerRKapasI 2010 Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy. Acta Neuropathol 121 39 57

25. BaringerJRPrusinerSB 1978 Experimental scrapie in mice: ultrastructural observations. Ann Neurol 4 205 211

26. CanelloTFridKGabizonRLisaSFriedlerA 2010 Oxidation of Helix-3 methionines precedes the formation of PK resistant PrP. PLoS Pathog 6 e1000977

27. PanKMStahlNPrusinerSB 1992 Purification and properties of the cellular prion protein from Syrian hamster brain. Protein Sci 1 1343 1352

28. TellingGCScottMMastrianniJGabizonRTorchiaM 1995 Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell 83 79 90

29. ShmerlingDHegyiIFischerMBlattlerTBrandnerS 1998 Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions. Cell 93 203 214

30. LasmezasCIDeslysJPRobainOJaeglyABeringueV 1997 Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 275 402 405

31. LegnameGNguyenHOBaskakovIVCohenFEDearmondSJ 2005 Strain-specified characteristics of mouse synthetic prions. Proc Natl Acad Sci U S A 102 2168 2173

32. HarveyBKRichieCTHofferBJAiravaaraM 2010 Transgenic animal models of neurodegeneration based on human genetic studies. J Neural Transm 118 27 45

33. AsheKHZahsKR 2010 Probing the biology of Alzheimer's disease in mice. Neuron 66 631 645

34. HarrisDAChiesaRDrisaldiBQuaglioEMigheliA 2000 A transgenic model of a familial prion disease. Arch Virol Suppl 103 112

35. ZanussoGFarinazzoAPrelliFFioriniMGelatiM 2004 Identification of distinct N-terminal truncated forms of prion protein in different Creutzfeldt-Jakob disease subtypes. J Biol Chem 279 38936 38942

36. CapellariSParchiPRussoCMSanfordJSyMS 2000 Effect of the E200K mutation on prion protein metabolism. Comparative study of a cell model and human brain. Am J Pathol 157 613 622

37. SimonESKahanaEChapmanJTrevesTAGabizonR 2000 Creutzfeldt-Jakob disease profile in patients homozygous for the PRNP E200K mutation. Ann Neurol 47 257 260

38. ForloniGSalmonaMMarconGTagliaviniF 2009 Tetracyclines and prion infectivity. Infect Disord Drug Targets 9 23 30

39. HavivYAvrahamiDOvadiaHBen-HurTGabizonR 2008 Induced neuroprotection independently from PrPSc accumulation in a mouse model for prion disease treated with simvastatin. Arch Neurol 65 762 775

40. RyouCLegnameGPeretzDCraigJCBaldwinMA 2003 Differential inhibition of prion propagation by enantiomers of quinacrine. Lab Invest 83 837 843

41. PeretzDWilliamsonRAKanekoKVergaraJLeclercE 2001 Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature 412 739 743

42. WhiteMDMallucciGR 2009 RNAi for the treatment of prion disease: a window for intervention in neurodegeneration? CNS Neurol Disord Drug Targets 8 342 352

43. BuelerHFischerMLangYBluethmannHLippHP 1992 Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356 577 582

44. ScottMGrothDFosterDTorchiaMYangSL 1993 Propagation of prions with artificial properties in transgenic mice expressing chimeric PrP genes. Cell 73 979 988

45. StahelPFShohamiEYounisFMKariyaKOttoVI 2000 Experimental closed head injury: analysis of neurological outcome, blood-brain barrier dysfunction, intracranial neutrophil infiltration, and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines. J Cereb Blood Flow Metab 20 369 380

46. PiroJRHarrisBTNishinaKSotoCMoralesR 2009 Prion protein glycosylation is not required for strain-specific neurotropism. J Virol 83 5321 5328

47. TzabanSFriedlanderGSchonbergerOHoronchikLYedidiaY 2002 Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry 41 12868 12875