Protease-Resistant Prions Selectively Decrease Shadoo Protein
The central event in prion diseases is the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrPSc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrPC, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrPSc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrPSc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrPSc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrPSc during prion disease.
Vyšlo v časopise:
Protease-Resistant Prions Selectively Decrease Shadoo Protein. PLoS Pathog 7(11): e32767. doi:10.1371/journal.ppat.1002382
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002382
Souhrn
The central event in prion diseases is the conformational conversion of the cellular prion protein (PrPC) into PrPSc, a partially protease-resistant and infectious conformer. However, the mechanism by which PrPSc causes neuronal dysfunction remains poorly understood. Levels of Shadoo (Sho), a protein that resembles the flexibly disordered N-terminal domain of PrPC, were found to be reduced in the brains of mice infected with the RML strain of prions [1], implying that Sho levels may reflect the presence of PrPSc in the brain. To test this hypothesis, we examined levels of Sho during prion infection using a variety of experimental systems. Sho protein levels were decreased in the brains of mice, hamsters, voles, and sheep infected with different natural and experimental prion strains. Furthermore, Sho levels were decreased in the brains of prion-infected, transgenic mice overexpressing Sho and in infected neuroblastoma cells. Time-course experiments revealed that Sho levels were inversely proportional to levels of protease-resistant PrPSc. Membrane anchoring and the N-terminal domain of PrP both influenced the inverse relationship between Sho and PrPSc. Although increased Sho levels had no discernible effect on prion replication in mice, we conclude that Sho is the first non-PrP marker specific for prion disease. Additional studies using this paradigm may provide insight into the cellular pathways and systems subverted by PrPSc during prion disease.
Zdroje
1. WattsJCDrisaldiBNgVYangJStromeB 2007 The CNS glycoprotein Shadoo has PrPC-like protective properties and displays reduced levels in prion infections. EMBO J 26 4038 4050
2. PrusinerSB 1998 Prions. Proc Natl Acad Sci USA 95 13363 13383
3. PrusinerSB 1982 Novel proteinaceous infectious particles cause scrapie. Science 216 136 144
4. BüelerHAguzziASailerAGreinerR-AAutenriedP 1993 Mice devoid of PrP are resistant to scrapie. Cell 73 1339 1347
5. SailerABüelerHFischerMAguzziAWeissmannC 1994 No propagation of prions in mice devoid of PrP. Cell 77 967 968
6. Schmitt-UlmsGHansenKLiuJCowdreyCYangJ 2004 Time-controlled transcardiac perfusion cross-linking for the study of protein interactions in complex tissues. Nat Biotechnol 22 724 731
7. WattsJCWestawayD 2007 The prion protein family: diversity, rivalry, and dysfunction. Biochim Biophys Acta 1772 654 672
8. WattsJCHuoHBaiYEhsaniSJeonAH 2009 Interactome analyses identify ties of PrP and its mammalian paralogs to oligomannosidic N-glycans and endoplasmic reticulum-derived chaperones. PLoS Pathog 5 e1000608
9. MooreRCLeeIYSilvermanGLHarrisonPMStromeR 1999 Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. J Mol Biol 292 797 817
10. BehrensAGenoudNNaumannHRülickeTJanettF 2002 Absence of the prion protein homologue Doppel causes male sterility. EMBO J 21 3652 3658
11. PremzlMSangiorgioLStrumboBMarshall GravesJASimonicT 2003 Shadoo, a new protein highly conserved from fish to mammals and with similarity to prion protein. Gene 314 89 102
12. MoHMooreRCCohenFEWestawayDPrusinerSB 2001 Two different neurodegenerative diseases caused by proteins with similar structures. Proc Natl Acad Sci USA 98 2352 2357
13. PeretzDWilliamsonRAMatsunagaYSerbanHPinillaC 1997 A conformational transition at the N-terminus of the prion protein features in formation of the scrapie isoform. J Mol Biol 273 614 622
14. BaumannFTolnayMBrabeckCPahnkeJKlozU 2007 Lethal recessive myelin toxicity of prion protein lacking its central domain. EMBO J 26 538 547
15. LiAChristensenHMStewartLRRothKAChiesaR 2007 Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105–125. EMBO J 26 548 558
16. SakthiveluVSeidelRPWinklhoferKFTatzeltJ 2011 Conserved stress-protective activity between prion protein and shadoo. J Biol Chem 286 8901 8908
17. ChenSGTeplowDBParchiPTellerJKGambettiP 1995 Truncated forms of the human prion protein in normal brain and in prion diseases. J Biol Chem 270 19173 19180
18. TaraboulosARaeberAJBorcheltDRSerbanDPrusinerSB 1992 Synthesis and trafficking of prion proteins in cultured cells. Mol Biol Cell 3 851 863
19. DronMMoudjouMChapuisJSalamatMKBernardJ 2010 Endogenous proteolytic cleavage of disease-associated prion protein to produce C2 fragments is strongly cell- and tissue-dependent. J Biol Chem 285 10252 10264
20. YoungRPassetBVilotteMCribiuEPBeringueV 2009 The prion or the related Shadoo protein is required for early mouse embryogenesis. FEBS Lett 583 3296 3300
21. BeckJACampbellTAAdamsonGPoulterMUphillJB 2008 Association of a null allele of SPRN with variant Creutzfeldt-Jakob disease. J Med Genet 45 813 817
22. LloydSEGrizenkovaJPotaHCollingeJ 2009 Shadoo (Sprn) and prion disease incubation time in mice. Mamm Genome 20 367 374
23. DaudeNWohlgemuthSRogaevaEFaridAHHeatonM 2009 Frequent missense and insertion/deletion polymorphisms in the ovine Shadoo gene parallel species-specific variation in PrP. PLoS ONE 4 e6538
24. StewartPShenCZhaoDGoldmannW 2009 Genetic analysis of the SPRN gene in ruminants reveals polymorphisms in the alanine-rich segment of shadoo protein. J Gen Virol 90 2575 2580
25. HopeJWoodSCBirkettCRChongABruceME 1999 Molecular analysis of ovine prion protein identifies similarities between BSE and an experimental isolate of natural scrapie, CH1641. J Gen Virol 80 1 4
26. GehlenborgNHwangDLeeIYYooHBaxterD 2009 The Prion Disease Database: a comprehensive transcriptome resource for systems biology research in prion diseases. Database (Oxford) bap011
27. GossnerAGBennetNHunterNHopkinsJ 2009 Differential expression of Prnp and Sprn in scrapie infected sheep also reveals Prnp genotype specific differences. Biochem Biophys Res Commun 378 862 866
28. DaudeNNgVWattsJCGenovesiSGlavesJP 2010 Wild-type Shadoo proteins convert to amyloid-like forms under native conditions. J Neurochem 113 92 104
29. DickinsonAGFraserH 1979 An assessment of the genetics of scrapie in sheep and mice. PrusinerSBHadlowWJ Slow Transmissible Diseases of the Nervous System, Vol 1 New York Academic Press 367 386
30. DickinsonAGMeikleVMH 1969 A comparison of some biological characteristics of the mouse-passaged scrapie agents, 22A and ME7. Genet Res 13 213 225
31. BruceMChreeAMcConnellIFosterJPearsonG 1994 Transmission of bovine spongiform encephalopathy and scrapie to mice: strain variation and the species barrier. Philos Trans R Soc Lond B Biol Sci 343 405 411
32. BruceMEDickinsonAG 1985 Genetic control of amyloid plaque production and incubation period in scrapie-infected mice. J Neuropathol Exp Neurol 44 285 294
33. KimberlinRHColeSWalkerCA 1987 Temporary and permanent modifications to a single strain of mouse scrapie on transmission to rats and hamsters. J Gen Virol 68 1875 1881
34. BessenRAMarshRF 1992 Identification of two biologically distinct strains of transmissible mink encephalopathy in hamsters. J Gen Virol 73 329 334
35. BosquePJPrusinerSB 2000 Cultured cell sublines highly susceptible to prion infection. J Virol 74 4377 4386
36. MahalSPBakerCADemczykCASmithEWJuliusC 2007 Prion strain discrimination in cell culture: the cell panel assay. Proc Natl Acad Sci USA 104 20908 20913
37. SaborioGPPermanneBSotoC 2001 Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411 810 813
38. MooreRCMastrangeloPBouzamondoEHeinrichCLegnameG 2001 Doppel-induced cerebellar degeneration in transgenic mice. Proc Natl Acad Sci USA 98 15288 15293
39. Sturchler-PierratCAbramowskiDDukeMWiederholdKHMistlC 1997 Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci USA 94 13287 13292
40. ChishtiMAYangDSJanusCPhinneyALHorneP 2001 Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 276 21562 21570
41. HsiaoKKScottMFosterDGrothDFDeArmondSJ 1990 Spontaneous neurodegeneration in transgenic mice with mutant prion protein. Science 250 1587 1590
42. NazorKEKuhnFSewardTGreenMZwaldD 2005 Immunodetection of disease-associated mutant PrP, which accelerates disease in GSS transgenic mice. EMBO J 24 2472 2480
43. HsiaoKKGrothDScottMYangS-LSerbanH 1994 Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein. Proc Natl Acad Sci USA 91 9126 9130
44. TellingGCHagaTTorchiaMTremblayPDeArmondSJ 1996 Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice. Genes Dev 10 1736 1750
45. ColbyDWWainRBaskakovIVLegnameGPalmerCG 2010 Protease-sensitive synthetic prions. PLoS Pathog 6 e1000736
46. WilhamJMOrruCDBessenRAAtarashiRSanoK 2010 Rapid end-point quantitation of prion seeding activity with sensitivity comparable to bioassays. PLoS Pathog 6 e1001217
47. ColbyDWZhangQWangSGrothDLegnameG 2007 Prion detection by an amyloid seeding assay. Proc Natl Acad Sci USA 104 20914 20919
48. WangHWanJWangWWangDLiS 2011 Overexpression of Shadoo protein in transgenic mice does not impact the pathogenesis of scrapie. Neurosci Lett 496 1 4
49. SupattaponeSMuramotoTLegnameGMehlhornICohenFE 2001 Identification of two prion protein regions that modify scrapie incubation time. J Virol 75 1408 1413
50. StöhrJWattsJCLegnameGOehlerALemusA Spontaneous generation of anchorless prions in transgenic mice. Proc Natl Acad Sci USA (In press)
51. NonnoRDi BariMACardoneFVaccariGFazziP 2006 Efficient transmission and characterization of Creutzfeldt-Jakob disease strains in bank voles. PLoS Pathog 2 e12
53. CronierSGrosNTattumMHJacksonGSClarkeAR 2008 Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem J 416 297 305
54. YadavalliRGuttmannRPSewardT Centers AP, Williamson RA, et al. 2004 Calpain-dependent endoproteolytic cleavage of PrPSc modulates scrapie prion propagation. J Biol Chem 279 21948 21956
54. WestawayDGenovesiSDaudeNBrownRLauA 2011 Down-regulation of shadoo in prion infections traces a pre-clinical event inversely related to PrPSc accumulation. PLoS Pathog 7 e1002391
55. LampoEVan den BroeckWWillemarckNVan PouckeMCasteleynCR 2011 Distribution of the Shadoo protein in the ovine brain assessed by immunohistochemistry. Res Vet Sci 90 372 378
56. MiyazawaKManuelidisL 2010 Agent-specific Shadoo responses in transmissible encephalopathies. J Neuroimmune Pharmacol 5 155 163
57. ZouWQPuotiGXiaoXYuanJQingL 2010 Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein. Ann Neurol 68 162 172
58. OttoMWiltfangJCepekLNeumannMMollenhauerB 2002 Tau protein and 14-3-3 protein in the differential diagnosis of Creutzfeldt-Jakob disease. Neurology 58 192 197
59. GodsaveSFWilleHKujalaPLatawiecDDeArmondSJ 2008 Cryo-immunogold electron microscopy for prions: toward identification of a conversion site. J Neurosci 28 12489 12499
60. PereraWSHooperNM 2001 Ablation of the metal ion-induced endocytosis of the prion protein by disease-associated mutation of the octarepeat region. Curr Biol 11 519 523
61. SunyachCJenADengJFitzgeraldKTFrobertY 2003 The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein. EMBO J 22 3591 3601
62. WeissmannCEnariMKlohnPCRossiDFlechsigE 2002 Transmission of prions. Proc Natl Acad Sci USA 99 16378 16383
63. MorelNSimonSFrobertYVollandHMourton-GillesC 2004 Selective and efficient immunoprecipitation of the disease-associated form of the prion protein can be mediated by nonspecific interactions between monoclonal antibodies and scrapie-associated fibrils. J Biol Chem 279 30143 30149
64. PastranaMASajnaniGOniskoBCastillaJMoralesR 2006 Isolation and characterization of a proteinase K-sensitive PrP(Sc) fraction. Biochemistry 45 15710 15717
65. TremblayPBallHLKanekoKGrothDHegdeRS 2004 Mutant PrPSc conformers induced by a synthetic peptide and several prion strains. J Virol 78 2088 2099
66. OlzschaHSchermannSMWoernerACPinkertSHechtMH 2011 Amyloid-like aggregates sequester numerous metastable proteins with essential cellular functions. Cell 144 67 78
67. KleeneRLoersGLangerJFrobertYBuckF 2007 Prion protein regulates glutamate-dependent lactate transport of astrocytes. J Neurosci 27 12331 12340
68. BignamiAPalladiniG 1966 Experimentally produced cerebral status spongiosus and continuous pseudorhythmic electroencephalographic discharges with a membrane-ATPase inhibitor in the rat. Nature 209 413 414
69. SafarJGScottMMonaghanJDeeringCDidorenkoS 2002 Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nat Biotechnol 20 1147 1150
70. WilliamsonRAPeretzDPinillaCBallHBastidasRB 1998 Mapping the prion protein using recombinant antibodies. J Virol 72 9413 9418
71. KascsakRJRubensteinRMerzPATonna-DeMasiMFerskoR 1987 Mouse polyclonal and monoclonal antibody to scrapie-associated fibril proteins. J Virol 61 3688 3693
72. CarlsonGAGoodmanPALovettMTaylorBAMarshallST 1988 Genetics and polymorphism of the mouse prion gene complex: control of scrapie incubation time. Mol Cell Biol 8 5528 5540
73. BüelerHFisherMLangYBluethmannHLippH-P 1992 Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 356 577 582
74. TamgüneyGGilesKGliddenDVLessardPWilleH 2008 Genes contributing to prion pathogenesis. J Gen Virol 89 1777 1788
75. CarlsonGAEbelingCYangS-LTellingGTorchiaM 1994 Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and transgenic mice. Proc Natl Acad Sci USA 91 5690 5694
76. TamgüneyGGilesKBouzamondo-BernsteinEBosquePJMillerMW 2006 Transmission of elk and deer prions to transgenic mice. J Virol 80 9104 9114
77. TamgüneyGMillerMWGilesKLemusAGliddenDV 2009 Transmission of scrapie and sheep-passaged bovine spongiform encephalopathy prions to transgenic mice expressing elk prion protein. J Gen Virol 90 1035 1047
78. TellingGCScottMHsiaoKKFosterDYangS-L 1994 Transmission of Creutzfeldt-Jakob disease from humans to transgenic mice expressing chimeric human-mouse prion protein. Proc Natl Acad Sci USA 91 9936 9940
79. GiassonBIDudaJEQuinnSMZhangBTrojanowskiJQ 2002 Neuronal α-synucleinopathy with severe movement disorder in mice expressing A53T human α-synuclein. Neuron 34 521 533
80. AllenBIngramETakaoMSmithMJJakesR 2002 Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J Neurosci 22 9340 9351
81. ScottMRKöhlerRFosterDPrusinerSB 1992 Chimeric prion protein expression in cultured cells and transgenic mice. Protein Sci 1 986 997
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