The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent

English version České info

Prions are unconventional infectious agents thought to be primarily composed of PrP^Sc, a multimeric misfolded conformer of the ubiquitously expressed host-encoded prion protein (PrP^C). They cause fatal neurodegenerative diseases in both animals and humans. The disease phenotype is not uniform within species, and stable, self-propagating variations in PrP^Sc conformation could encode this ‘strain’ diversity. However, much remains to be learned about the physical relationship between the infectious agent and PrP^Sc aggregation state, and how this varies according to the strain. We applied a sedimentation velocity technique to a panel of natural, biologically cloned strains obtained by propagation of classical and atypical sheep scrapie and BSE infectious sources in transgenic mice expressing ovine PrP. Detergent-solubilized, infected brain homogenates were used as starting material. Solubilization conditions were optimized to separate PrP^Sc aggregates from PrP^C. The distribution of PrP^Sc and infectivity in the gradient was determined by immunoblotting and mouse bioassay, respectively. As a general feature, a major proteinase K-resistant PrP^Sc peak was observed in the middle part of the gradient. This population approximately corresponds to multimers of 12–30 PrP molecules, if constituted of PrP only. For two strains, infectivity peaked in a markedly different region of the gradient. This most infectious component sedimented very slowly, suggesting small size oligomers and/or low density PrP^Sc aggregates. Extending this study to hamster prions passaged in hamster PrP transgenic mice revealed that the highly infectious, slowly sedimenting particles could be a feature of strains able to induce a rapidly lethal disease. Our findings suggest that prion infectious particles are subjected to marked strain-dependent variations, which in turn could influence the strain biological phenotype, in particular the replication dynamics.

Vyšlo v časopise: The Physical Relationship between Infectivity and Prion Protein Aggregates Is Strain-Dependent. PLoS Pathog 6(4): e32767. doi:10.1371/journal.ppat.1000859
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000859

Souhrn

Zdroje

1. CollingeJ

2001 Prion diseases of humans and animals: their causes and molecular basis. Annu Rev Neurosci 24 519 550

2. PrusinerSB

1998 Prions. Proc Natl Acad Sci U S A 95 13363 13383

3. WeissmannC

2004 The state of the prion. Nat Rev Microbiol 2 861 871

4. MallucciG

CollingeJ

2005 Rational targeting for prion therapeutics. Nat Rev Neurosci 6 23 34

5. CaugheyB

LansburyPT

2003 Protofibrils, pores, fibrils, and neurodegeneration: separating the responsible protein aggregates from the innocent bystanders. Annu Rev Neurosci 26 267 298

6. BoltonDC

McKinleyMP

PrusinerSB

1982 Identification of a protein that purifies with the scrapie prion. Science 218 1309 1311

7. BeringueV

VilotteJL

LaudeH

2008 Prion agent diversity and species barrier. Vet Res 39 47

8. BruceME

2003 TSE strain variation. Br Med Bull 66 99 108

9. CollingeJ

ClarkeAR

2007 A general model of prion strains and their pathogenicity. Science 318 930 936

10. TellingGC

ParchiP

DeArmondSJ

CortelliP

MontagnaP

1996 Evidence for the conformation of the pathologic isoform of the prion protein enciphering and propagating prion diversity. Science 274 2079 2082

11. BessenRA

MarshRF

1994 Distinct PrP properties suggest the molecular basis of strain variation in transmissible mink encephalopathy. J Virol 68 7859 7868

12. CaugheyB

RaymondGJ

BessenRA

1998 Strain-dependent differences in beta-sheet conformations of abnormal prion protein. J Biol Chem 273 32230 32235

13. ThomzigA

SpassovS

FriedrichM

NaumannD

BeekesM

2004 Discriminating scrapie and bovine spongiform encephalopathy isolates by infrared spectroscopy of pathological prion protein. J Biol Chem 279 33847 33854

14. CollingeJ

SidleKC

MeadsJ

IronsideJ

HillAF

1996 Molecular analysis of prion strain variation and the aetiology of ‘new variant’ CJD. Nature 383 685 690

15. SimVL

CaugheyB

2008 Ultrastructures and strain comparison of under-glycosylated scrapie prion fibrils. Neurobiol Aging

16. BessenRA

KociskoDA

RaymondGJ

NandanS

LansburyPT

1995 Non-genetic propagation of strain-specific properties of scrapie prion protein. Nature 375 698 700

17. CastillaJ

MoralesR

SaaP

BarriaM

GambettiP

2008 Cell-free propagation of prion strains. Embo J 27 2557 2566

18. RiesnerD

KellingsK

PostK

WilleH

SerbanH

1996 Disruption of prion rods generates 10-nm spherical particles having high alpha-helical content and lacking scrapie infectivity. J Virol 70 1714 1722

19. SafarJ

WangW

PadgettMP

CeroniM

PiccardoP

1990 Molecular mass, biochemical composition, and physicochemical behavior of the infectious form of the scrapie precursor protein monomer. Proc Natl Acad Sci U S A 87 6373 6377

20. SklaviadisTK

ManuelidisL

ManuelidisEE

1989 Physical properties of the Creutzfeldt-Jakob disease agent. J Virol 63 1212 1222

21. TateishiJ

KitamotoT

MohriS

SatohS

SatoT

2001 Scrapie removal using Planova virus removal filters. Biologicals 29 17 25

22. SunR

LiuY

ZhangH

ManuelidisL

2008 Quantitative recovery of scrapie agent with minimal protein from highly infectious cultures. Viral Immunol 21 293 302

23. SilveiraJR

RaymondGJ

HughsonAG

RaceRE

SimVL

2005 The most infectious prion protein particles. Nature 437 257 261

24. SomervilleRA

DunnAJ

1996 The association between PrP and infectivity in scrapie and BSE infected mouse brain. Arch Virol 141 275 289

25. SklaviadisT

DreyerR

ManuelidisL

1992 Analysis of Creutzfeldt-Jakob disease infectious fractions by gel permeation chromatography and sedimentation field flow fractionation. Virus Res 26 241 254

26. BrownDA

RoseJK

1992 Sorting of GPI-anchored proteins to glycolipid-enriched membrane subdomains during transport to the apical cell surface. Cell 68 533 544

27. le MaireM

ChampeilP

MollerJV

2000 Interaction of membrane proteins and lipids with solubilizing detergents. Biochim Biophys Acta 1508 86 111

28. TzabanS

FriedlanderG

SchonbergerO

HoronchikL

YedidiaY

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

29. LondonE

BrownDA

2000 Insolubility of lipids in triton X-100: physical origin and relationship to sphingolipid/cholesterol membrane domains (rafts). Biochim Biophys Acta 1508 182 195

30. EghiaianF

DaubenfeldT

QuenetY

van AudenhaegeM

BouinAP

2007 Diversity in prion protein oligomerization pathways results from domain expansion as revealed by hydrogen/deuterium exchange and disulfide linkage. Proc Natl Acad Sci U S A 104 7414 7419

31. MerzPA

SomervilleRA

WisniewskiHM

ManuelidisL

ManuelidisEE

1983 Scrapie-associated fibrils in Creutzfeldt-Jakob disease. Nature 306 474 476

32. LasmezasCI

DeslysJP

RobainO

JaeglyA

BeringueV

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

33. BeringueV

BencsikA

Le DurA

ReineF

LaiTL

2006 Isolation from cattle of a prion strain distinct from that causing bovine spongiform encephalopathy. PLoS Pathog 2 e112 doi:10.1371/journal.ppat.0020112

34. PrusinerSB

CochranSP

GrothDF

DowneyDE

BowmanKA

1982 Measurement of the scrapie agent using an incubation time interval assay. Ann Neurol 11 353 358

35. PastranaMA

SajnaniG

OniskoB

CastillaJ

MoralesR

2006 Isolation and characterization of a proteinase K-sensitive PrPSc fraction. Biochemistry 45 15710 15717

36. SafarJG

GeschwindMD

DeeringC

DidorenkoS

SattavatM

2005 Diagnosis of human prion disease. Proc Natl Acad Sci U S A 102 3501 3506

37. CronierS

GrosN

TattumMH

JacksonGS

ClarkeAR

2008 Detection and characterization of proteinase K-sensitive disease-related prion protein with thermolysin. Biochem J 416 297 305

38. SomervilleRA

CarpRI

1983 Altered scrapie infectivity estimates by titration and incubation period in the presence of detergents. J Gen Virol 64(Pt 9) 2045 2050

39. GabizonR

McKinleyMP

PrusinerSB

1987 Purified prion proteins and scrapie infectivity copartition into liposomes. Proc Natl Acad Sci U S A 84 4017 4021

40. ViletteD

AndreolettiO

ArcherF

MadelaineMF

VilotteJL

2001 Ex vivo propagation of infectious sheep scrapie agent in heterologous epithelial cells expressing ovine prion protein. Proc Natl Acad Sci U S A 98 4055 4059

41. Le DurA

BeringueV

AndreolettiO

ReineF

LaiTL

2005 A newly identified type of scrapie agent can naturally infect sheep with resistant PrP genotypes. Proc Natl Acad Sci U S A 102 16031 16036

42. BenestadSL

ArsacJN

GoldmannW

NoremarkM

2008 Atypical/Nor98 scrapie: properties of the agent, genetics, and epidemiology. Vet Res 39 19

43. ArsacJN

AndreolettiO

BilheudeJM

LacrouxC

BenestadSL

2007 Similar biochemical signatures and prion protein genotypes in atypical scrapie and Nor98 cases, France and Norway. Emerg Infect Dis 13 58 65

44. KlingebornM

WikL

SimonssonM

RenstromLH

OttingerT

2006 Characterization of proteinase K-resistant N- and C-terminally truncated PrP in Nor98 atypical scrapie. J Gen Virol 87 1751 1760

45. KleinTR

KirschD

KaufmannR

RiesnerD

1998 Prion rods contain small amounts of two host sphingolipids as revealed by thin-layer chromatography and mass spectrometry. Biol Chem 379 655 666

46. SafarJG

KellingsK

SerbanA

GrothD

CleaverJE

2005 Search for a prion-specific nucleic acid. J Virol 79 10796 10806

47. BarronRM

CampbellSL

KingD

BellonA

ChapmanKE

2007 High titers of transmissible spongiform encephalopathy infectivity associated with extremely low levels of PrPSc in vivo. J Biol Chem 282 35878 35886

48. CronierS

BeringueV

BellonA

PeyrinJM

LaudeH

2007 Prion strain- and species-dependent effects of antiprion molecules in primary neuronal cultures. J Virol 81 13794 13800

49. ThackrayAM

HopkinsL

BujdosoR

2007 Proteinase K-sensitive disease-associated ovine prion protein revealed by conformation-dependent immunoassay. Biochem J 401 475 483

50. DeleaultAM

DeleaultNR

HarrisBT

ReesJR

SupattaponeS

2008 The effects of prion protein proteolysis and disaggregation on the strain properties of hamster scrapie. J Gen Virol 89 2642 2650

51. BerardiVA

CardoneF

ValanzanoA

LuM

PocchiariM

2006 Preparation of soluble infectious samples from scrapie-infected brain: a new tool to study the clearance of transmissible spongiform encephalopathy agents during plasma fractionation. Transfusion 46 652 658

52. SafarJ

WilleH

ItriV

GrothD

SerbanH

1998 Eight prion strains have PrP(Sc) molecules with different conformations. Nat Med 4 1157 1165

53. de la MazaA

ParraJL

1997 Solubilizing effects caused by the nonionic surfactant dodecylmaltoside in phosphatidylcholine liposomes. Biophys J 72 1668 1675

54. LambengN

GrossmannM

ChatelainP

FuksB

2006 Solubilization and immunopurification of rat brain synaptic vesicle protein 2A with maintained binding properties. Neurosci Lett 398 107 112

55. LucheS

SantoniV

RabilloudT

2003 Evaluation of nonionic and zwitterionic detergents as membrane protein solubilizers in two-dimensional electrophoresis. Proteomics 3 249 253

56. RibosaII

Sanchez-LealJ

ComellesF

GarciaMT

1997 Solubilization of Large Unilamellar Liposomes by Alkyl Glycosides. J Colloid Interface Sci 187 443 446

57. SafarJG

WilleH

GeschwindMD

DeeringC

LatawiecD

2006 Human prions and plasma lipoproteins. Proc Natl Acad Sci U S A 103 11312 11317

58. TanakaM

CollinsSR

ToyamaBH

WeissmanJS

2006 The physical basis of how prion conformations determine strain phenotypes. Nature 442 585 589

59. LegnameG

NguyenHO

PeretzD

CohenFE

DeArmondSJ

2006 Continuum of prion protein structures enciphers a multitude of prion isolate-specified phenotypes. Proc Natl Acad Sci U S A 103 19105 19110

60. BeringueV

AndreolettiO

Le DurA

EssalmaniR

VilotteJL

2007 A bovine prion acquires an epidemic bovine spongiform encephalopathy strain-like phenotype on interspecies transmission. J Neurosci 27 6965 6971

61. VilotteJL

SoulierS

EssalmaniR

StinnakreMG

VaimanD

2001 Markedly increased susceptibility to natural sheep scrapie of transgenic mice expressing ovine prp. J Virol 75 5977 5984

62. PrusinerSB

ScottM

FosterD

PanKM

GrothD

1990 Transgenetic studies implicate interactions between homologous PrP isoforms in scrapie prion replication. Cell 63 673 686

63. SimonS

NugierJ

MorelN

BoutalH

CreminonC

2008 Rapid typing of transmissible spongiform encephalopathy strains with differential ELISA. Emerg Infect Dis 14 608 616

64. MoudjouM

TreguerE

RezaeiH

SabuncuE

NeuendorfE

2004 Glycan-controlled epitopes of prion protein include a major determinant of susceptibility to sheep scrapie. J Virol 78 9270 9276

65. PaquetS

DaudeN

CourageotMP

ChapuisJ

LaudeH

2007 PrPc does not mediate internalization of PrPSc but is required at an early stage for de novo prion infection of Rov cells. J Virol 81 10786 10791

66. BeringueV

Le DurA

TixadorP

ReineF

LepourryL

2008 Prominent and persistent extraneural infection in human PrP transgenic mice infected with variant CJD. PLoS ONE 3 e1419 doi:10.1371/journal.pone.0001419

67. HeckerR

TaraboulosA

ScottM

PanKM

YangSL

1992 Replication of distinct scrapie prion isolates is region specific in brains of transgenic mice and hamsters. Genes Dev 6 1213 1228