Biochemical Properties of Highly Neuroinvasive Prion Strains
Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.
Vyšlo v časopise:
Biochemical Properties of Highly Neuroinvasive Prion Strains. PLoS Pathog 8(2): e32767. doi:10.1371/journal.ppat.1002522
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1002522
Souhrn
Infectious prions propagate from peripheral entry sites into the central nervous system (CNS), where they cause progressive neurodegeneration that ultimately leads to death. Yet the pathogenesis of prion disease can vary dramatically depending on the strain, or conformational variant of the aberrantly folded and aggregated protein, PrPSc. Although most prion strains invade the CNS, some prion strains cannot gain entry and do not cause clinical signs of disease. The conformational basis for this remarkable variation in the pathogenesis among strains is unclear. Using mouse-adapted prion strains, here we show that highly neuroinvasive prion strains primarily form diffuse aggregates in brain and are noncongophilic, conformationally unstable in denaturing conditions, and lead to rapidly lethal disease. These neuroinvasive strains efficiently generate PrPSc over short incubation periods. In contrast, the weakly neuroinvasive prion strains form large fibrillary plaques and are stable, congophilic, and inefficiently generate PrPSc over long incubation periods. Overall, these results indicate that the most neuroinvasive prion strains are also the least stable, and support the concept that the efficient replication and unstable nature of the most rapidly converting prions may be a feature linked to their efficient spread into the CNS.
Zdroje
1. AguzziAPolymenidouM 2004 Mammalian prion biology. One century of evolving concepts. Cell 116 313 327
2. PrusinerSB 1982 Novel proteinaceous infectious particles cause scrapie. Science 216 136 144
3. DeleaultNRHarrisBTReesJRSupattaponeS 2007 Formation of native prions from minimal components in vitro. Proc Natl Acad Sci U S A 104 9741 9746
4. WangFWangXYuanCGMaJ 2010 Generating a prion with bacterially expressed recombinant prion protein. Science 327 1132 1135
5. MakaravaNKovacsGGBocharovaOSavtchenkoRAlexeevaI 2010 Recombinant prion protein induces a new transmissible prion disease in wild-type animals. Acta Neuropathol 119 177 187
6. FraserHDickinsonAG 1968 The sequential development of the brain lesion of scrapie in three strains of mice. J Comp Pathol 78 301 311
7. FraserHDickinsonAG 1973 Scrapie in mice. Agent-strain differences in the distribution and intensity of grey matter vacuolation. J Comp Pathol 83 29 40
8. BruceMEMcBridePAFarquharCF 1989 Precise targeting of the pathology of the sialoglycoprotein, PrP, and vacuolar degeneration in mouse scrapie. Neurosci Lett 102 1 6
9. CollingeJClarkeAR 2007 A general model of prion strains and their pathogenicity. Science 318 930 936
10. TellingGC 2011 Transgenic mouse models and prion strains. Top Curr Chem 305 79 99
11. BessenRAMarshRF 1992 Biochemical and physical properties of the prion protein from two strains of the transmissible mink encephalopathy agent. J Virol 66 2096 2101
12. HillAFJoinerSBeckJACampbellTADickinsonA 2006 Distinct glycoform ratios of protease resistant prion protein associated with PRNP point mutations. Brain 129 676 685
13. SafarJWilleHItriVGrothDSerbanH 1998 Eight prion strains have PrPSc molecules with different conformations. Nat Med 4 1157 1165
14. PeretzDWilliamsonRALegnameGMatsunagaYVergaraJ 2002 A change in the conformation of prions accompanies the emergence of a new prion strain. Neuron 34 921 932
15. SmirnovasVBaronGSOfferdahlDKRaymondGJCaugheyB 2011 Structural organization of brain-derived mammalian prions examined by hydrogen-deuterium exchange. Nat Struct Mol Biol 18 504 506
16. BruceMEMcConnellIFraserHDickinsonAG 1991 The disease characteristics of different strains of scrapie in Sinc congenic mouse lines: implications for the nature of the agent and host control of pathogenesis. J Gen Virol 72 595 603
17. LegnameGNguyenHOPeretzDCohenFEDeArmondSJ 2006 Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc Natl Acad Sci U S A 103 19105 19110
18. AyersJISchuttCRShikiyaRAAguzziAKincaidAE 2011 The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease. PLoS Pathog 7 e1001317
19. SilveiraJRRaymondGJHughsonAGRaceRESimVL 2005 The most infectious prion protein particles. Nature 437 257 261
20. TixadorPHerzogLReineFJaumainEChapuisJ 2010 The physical relationship between infectivity and prion protein aggregates is strain-dependent. PLoS Pathog 6 e1000859
21. TzabanSFriedlanderGSchonbergerOHoronchikLYedidiaY 2002 Protease-sensitive scrapie prion protein in aggregates of heterogeneous sizes. Biochemistry 41 12868 12875
22. PastranaMASajnaniGOniskoBCastillaJMoralesR 2006 Isolation and Characterization of a Proteinase K-Sensitive PrP(Sc) Fraction. Biochemistry 45 15710 15717
23. SafarJGGeschwindMDDeeringCDidorenkoSSattavatM 2005 Diagnosis of human prion disease. Proc Natl Acad Sci U S A 102 3501 3506
24. KimberlinRHWalkerCA 1988 Incubation periods in six models of intraperitoneally injected scrapie depend mainly on the dynamics of agent replication within the nervous system and not the lymphoreticular system. J Gen Virol 69 2953 2960
25. KleinMAFriggRRaeberAJFlechsigEHegyiI 1998 PrP expression in B lymphocytes is not required for prion neuroinvasion. Nat Med 4 1429 1433
26. GlatzelMAguzziA 2000 PrP(C) expression in the peripheral nervous system is a determinant of prion neuroinvasion. J Gen Virol 81 2813 2821
27. GlatzelMHeppnerFLAlbersKMAguzziA 2001 Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31 25 34
28. HaikSFaucheuxBASazdovitchVPrivatNKemenyJL 2003 The sympathetic nervous system is involved in variant Creutzfeldt-Jakob disease. Nat Med 9 1121 1122
29. BartzJCKincaidAEBessenRA 2002 Retrograde transport of transmissible mink encephalopathy within descending motor tracts. J Virol 76 5759 5768
30. BartzJCKincaidAEBessenRA 2003 Rapid prion neuroinvasion following tongue infection. J Virol 77 583 591
31. PrinzMHeikenwalderMJuntTSchwarzPGlatzelM 2003 Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425 957 962
32. KimberlinRHWalkerCA 1989 Pathogenesis of scrapie in mice after intragastric infection. Virus Res 12 213 220
33. BeekesMMcBridePABaldaufE 1998 Cerebral targeting indicates vagal spread of infection in hamsters fed with scrapie. J Gen Virol 79 Part 3 601 607
34. KimberlinRHWalkerCA 1986 Pathogenesis of scrapie (strain 263 K) in hamsters infected intracerebrally, intraperitoneally or intraocularly. J Gen Virol 67 255 263
35. MabbottNABruceMEBottoMWalportMJPepysMB 2001 Temporary depletion of complement component C3 or genetic deficiency of C1q significantly delays onset of scrapie. Nat Med 7 485 487
36. KleinMAKaeserPSSchwarzPWeydHXenariosI 2001 Complement facilitates early prion pathogenesis. Nat Med 7 488 492
37. ZabelMDHeikenwalderMPrinzMArrighiISchwarzP 2007 Stromal complement receptor CD21/35 facilitates lymphoid prion colonization and pathogenesis. J Immunol 179 6144 6152
38. CollisSCKimberlinRH 1985 Long-term persistence of scrapie infection in mouse spleens in the absence of clinical disease. FEMS Microbiol Lett 29 111 114
39. MooreRCHopeJMcBridePAMcConnellISelfridgeJ 1998 Mice with gene targetted prion protein alterations show that Prnp, Sinc and Prni are congruent. Nat Genet 18 118 125
40. MabbottNAMcGovernGJeffreyMBruceME 2002 Temporary blockade of the tumor necrosis factor receptor signaling pathway impedes the spread of scrapie to the brain. J Virol 76 5131 5139
41. MabbottNAWilliamsAFarquharCFPasparakisMKolliasG 2000 Tumor necrosis factor alpha-deficient, but not interleukin-6-deficient, mice resist peripheral infection with scrapie. J Virol 74 3338 3344
42. MabbottNAYoungJMcConnellIBruceME 2003 Follicular dendritic cell dedifferentiation by treatment with an inhibitor of the lymphotoxin pathway dramatically reduces scrapie susceptibility. J Virol 77 6845 6854
43. SadowskiMJPankiewiczJPrelliFScholtzovaHSpinnerDS 2009 Anti-PrP Mab 6D11 suppresses PrP(Sc) replication in prion infected myeloid precursor line FDC-P1/22 L and in the lymphoreticular system in vivo. Neurobiol Dis 34 267 278
44. GodsaveSFWilleHKujalaPLatawiecDDeArmondSJ 2008 Cryo-immunogold electron microscopy for prions: toward identification of a conversion site. J Neurosci 28 12489 12499
45. JeffreyMGoodsirCMBruceMEMcBridePAFraserJR 1997 In vivo toxicity of prion protein in murine scrapie: ultrastructural and immunogold studies. Neuropathol Appl Neurobiol 23 93 101
46. PeretzDScottMRGrothDWilliamsonRABurtonDR 2001 Strain-specified relative conformational stability of the scrapie prion protein. Protein Sci 10 854 863
47. TanakaMChienPNaberNCookeRWeissmanJS 2004 Conformational variations in an infectious protein determine prion strain differences. Nature 428 323 328
48. MabbottNAMacPhersonGG 2006 Prions and their lethal journey to the brain. Nat Rev Microbiol 4 201 211
49. BeringueVLe DurATixadorPReineFLepourryL 2008 Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS ONE 3 e1419
50. KlingebornMRaceBMeade-WhiteKDRosenkeRStriebelJF 2011 Crucial role for prion protein membrane anchoring in the neuroinvasion and neural spread of prion infection. J Virol 85 1484 1494
51. CaugheyBLansburyPTJr 2003 Protofibrils, Pores, Fibrils, and Neurodegeneration: Separating the Responsible Protein Aggregates from the Innocent Bystanders. Annu Rev Neurosci 26 267 98
52. WadsworthJDAsanteEADesbruslaisMLinehanJMJoinerS 2004 Human prion protein with valine 129 prevents expression of variant CJD phenotype. Science 306 1793 1796
53. PiccardoPMansonJCKingDGhettiBBarronRM 2007 Accumulation of prion protein in the brain that is not associated with transmissible disease. Proc Natl Acad Sci U S A 104 4712 4717
54. MontrasioFFriggRGlatzelMKleinMAMackayF 2000 Impaired prion replication in spleens of mice lacking functional follicular dendritic cells. Science 288 1257 1259
55. MabbottNAMackayFMinnsFBruceME 2000 Temporary inactivation of follicular dendritic cells delays neuroinvasion of scrapie [letter]. Nat Med 6 719 720
56. BruceME 1985 Agent replication dynamics in a long incubation period model of mouse scrapie. J Gen Virol 66 2517 2522
57. CronierSGrosNTattumMHJacksonGSClarkeAR 2008 Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem J 416 297 305
58. KimCHaldimanTCohenYChenWBlevinsJ 2011 Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate. PLoS Pathog 7 e1002242
59. ThackrayAMHopkinsLKleinMABujdosoR 2007 Mouse-adapted ovine scrapie prion strains are characterized by different conformers of PrPSc. J Virol 81 12119 12127
60. SchutzAKSoragniAHornemannSAguzziAErnstM 2011 The amyloid-Congo red interface at atomic resolution. Angew Chem Int Ed Engl 50 5956 5960
61. PrusinerSBMcKinleyMPBowmanKABoltonDCBendheimPE 1983 Scrapie prions aggregate to form amyloid-like birefringent rods. Cell 35 349 358
62. McKinleyMPMeyerRKKenagaLRahbarFCotterR 1991 Scrapie prion rod formation in vitro requires both detergent extraction and limited proteolysis. J Virol 65 1340 1351
63. SigurdsonCJMancoGSchwarzPLiberskiPHooverEA 2006 Strain fidelity of chronic wasting disease upon murine adaptation. J Virol 80 12303 12311
64. TanakaMCollinsSRToyamaBHWeissmanJS 2006 The physical basis of how prion conformations determine strain phenotypes. Nature 442 585 589
65. DerdowskiASindiSSKlaipsCLDiSalvoSSerioTR 2010 A size threshold limits prion transmission and establishes phenotypic diversity. Science 330 680 683
66. KnowlesTPWaudbyCADevlinGLCohenSIAguzziA 2009 An analytical solution to the kinetics of breakable filament assembly. Science 326 1533 1537
67. SigurdsonCJNilssonKPHornemannSHeikenwalderMMancoG 2009 De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis. Proc Natl Acad Sci U S A 106 304 309
68. TaraboulosAJendroskaKSerbanDYangSLDeArmondSJ 1992 Regional mapping of prion proteins in brain. Proc Natl Acad Sci U S A 89 7620 7624
69. PolymenidouMMoosRScottMSigurdsonCShiYZ 2008 The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLoS ONE 3 e3872
70. WadsworthJDFJoinerSHillAFCampbellTADesbruslaisM 2001 Tissue distribution of protease resistant prion protein in variant CJD using a highly sensitive immuno-blotting assay. Lancet 358 171 180
Štítky
Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
PLOS Pathogens
2012 Číslo 2
- Parazitičtí červi v terapii Crohnovy choroby a dalších zánětlivých autoimunitních onemocnění
- Očkování proti virové hemoragické horečce Ebola experimentální vakcínou rVSVDG-ZEBOV-GP
- Koronavirus hýbe světem: Víte jak se chránit a jak postupovat v případě podezření?
Najčítanejšie v tomto čísle
- Discrete Cyclic di-GMP-Dependent Control of Bacterial Predation versus Axenic Growth in
- Characterising the Mucosal and Systemic Immune Responses to Experimental Human Hookworm Infection
- How Do Microbial Pathogens Make s?
- Substance P Causes Seizures in Neurocysticercosis