Protease-Sensitive Synthetic Prions

English version České info

Prions arise when the cellular prion protein (PrP^C) undergoes a self-propagating conformational change; the resulting infectious conformer is designated PrP^Sc. Frequently, PrP^Sc is protease-resistant but protease-sensitive (s) prions have been isolated in humans and other animals. We report here that protease-sensitive, synthetic prions were generated in vitro during polymerization of recombinant (rec) PrP into amyloid fibers. In 22 independent experiments, recPrP amyloid preparations, but not recPrP monomers or oligomers, transmitted disease to transgenic mice (n = 164), denoted Tg9949 mice, that overexpress N-terminally truncated PrP. Tg9949 control mice (n = 174) did not spontaneously generate prions although they were prone to late-onset spontaneous neurological dysfunction. When synthetic prion isolates from infected Tg9949 mice were serially transmitted in the same line of mice, they exhibited sPrP^Sc and caused neurodegeneration. Interestingly, these protease-sensitive prions did not shorten the life span of Tg9949 mice despite causing extensive neurodegeneration. We inoculated three synthetic prion isolates into Tg4053 mice that overexpress full-length PrP; Tg4053 mice are not prone to developing spontaneous neurological dysfunction. The synthetic prion isolates caused disease in 600–750 days in Tg4053 mice, which exhibited sPrP^Sc. These novel synthetic prions demonstrate that conformational changes in wild-type PrP can produce mouse prions composed exclusively of sPrP^Sc.

Vyšlo v časopise: Protease-Sensitive Synthetic Prions. PLoS Pathog 6(1): e32767. doi:10.1371/journal.ppat.1000736
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1000736

Souhrn

Zdroje

1. PrusinerSB

1998 Prions. Proc Natl Acad Sci USA 95 13363 13383

2. OeschB

WestawayD

WälchliM

McKinleyMP

KentSBH

1985 A cellular gene encodes scrapie PrP 27–30 protein. Cell 40 735 746

3. PrusinerSB

1982 Novel proteinaceous infectious particles cause scrapie. Science 216 136 144

4. McKinleyMP

BoltonDC

PrusinerSB

1983 A protease-resistant protein is a structural component of the scrapie prion. Cell 35 57 62

5. MeyerRK

McKinleyMP

BowmanKA

BraunfeldMB

BarryRA

1986 Separation and properties of cellular and scrapie prion proteins. Proc Natl Acad Sci USA 83 2310 2314

6. BrownP

Coker-VannM

PomeroyK

FrankoM

AsherDM

1986 Diagnosis of Creutzfeldt-Jakob disease by Western blot identification of marker protein in human brain tissue. N Engl J Med 314 547 551

7. SafarJ

WilleH

ItriV

GrothD

SerbanH

1998 Eight prion strains have PrPSc molecules with different conformations. Nat Med 4 1157 1165

8. SafarJG

GeschwindMD

DeeringC

DidorenkoS

SattavatM

2005 Diagnosis of human prion disease. Proc Natl Acad Sci USA 102 3501 3506

9. GambettiP

DongZ

YuanJ

XiaoX

ZhengM

2008 A novel human disease with abnormal prion protein sensitive to protease. Ann Neurol 63 697 708

10. HeadMW

KnightR

ZeidlerM

YullH

BarlowA

In press A case of protease sensitive prionopathy in a patient in the United Kingdom. Neuropathol Appl Neurobiol

11. HallDA

LeeheyMA

FilleyCM

SteinbartE

MontineT

2005 PRNP H187R mutation associated with neuropsychiatric disorders in childhood and dementia. Neurology 64 1304 1306

12. BenestadSL

SarradinP

ThuB

SchonheitJ

TranulisMA

2003 Cases of scrapie with unusual features in Norway and designation of a new type, Nor98. Vet Rec 153 202 208

13. OrgeL

GaloA

MachadoC

LimaC

OchoaC

2004 Identification of putative atypical scrapie in sheep in Portugal. J Gen Virol 85 3487 3491

14. 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

15. HsiaoKK

ScottM

FosterD

GrothDF

DeArmondSJ

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

16. TremblayP

BallHL

KanekoK

GrothD

HegdeRS

2004 Mutant PrPSc conformers induced by a synthetic peptide and several prion strains. J Virol 78 2088 2099

17. TellingGC

HagaT

TorchiaM

TremblayP

DeArmondSJ

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

18. InouyeH

BondJ

BaldwinMA

BallHL

PrusinerSB

2000 Structural changes in a hydrophobic domain of the prion protein induced by hydration and by Ala→Val and Pro→Leu substitutions. J Mol Biol 300 1283 1296

19. LawsDD

BitterH-ML

LiuK

BallHL

KanekoK

2001 Solid-state NMR studies of the secondary structure of a mutant prion protein fragment of 55 residues that induces neurodegeneration. Proc Natl Acad Sci USA 98 11686 11690

20. KanekoK

BallHL

WilleH

ZhangH

GrothD

2000 A synthetic peptide initiates Gerstmann-Sträussler-Scheinker (GSS) disease in transgenic mice. J Mol Biol 295 997 1007

21. SupattaponeS

MuramotoT

LegnameG

MehlhornI

CohenFE

2001 Identification of two prion protein regions that modify scrapie incubation time. J Virol 75 1408 1413

22. LegnameG

BaskakovIV

NguyenH-OB

RiesnerD

CohenFE

2004 Synthetic mammalian prions. Science 305 673 676

23. LegnameG

NguyenH-OB

BaskakovIV

CohenFE

DeArmondSJ

2005 Strain-specified characteristics of mouse synthetic prions. Proc Natl Acad Sci USA 102 2168 2173

24. LegnameG

NguyenH-OB

PeretzD

CohenFE

DeArmondSJ

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

25. SafarJG

ScottM

MonaghanJ

DeeringC

DidorenkoS

2002 Measuring prions causing bovine spongiform encephalopathy or chronic wasting disease by immunoassays and transgenic mice. Nat Biotechnol 20 1147 1150

26. ColbyDW

ZhangQ

WangS

GrothD

LegnameG

2007 Prion detection by an amyloid seeding assay. Proc Natl Acad Sci USA 104 20914 20919

27. ColbyDW

GilesK

LegnameG

WilleH

BaskakovIV

2009 Design and construction of diverse mammalian prion strains. Proc Natl Acad Sci USA 106 20417 20422

28. CarlsonGA

EbelingC

YangS-L

TellingG

TorchiaM

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

29. DeArmondSJ

IronsideJW

Bouzamondo-BernsteinE

PeretzD

FraserJR

2004 Neuropathology of prion diseases.

PrusinerSB

Prion Biology and Diseases. 2nd ed Cold Spring Harbor Cold Spring Harbor Laboratory Press 777 856

30. RogersDR

1965 Screening for amyloid with the thioflavin-t fluorescent method. Am J Clin Pathol 44 59 61

31. BaskakovIV

LegnameG

PrusinerSB

CohenFE

2001 Folding of prion protein to its native α-helical conformation is under kinetic control. J Biol Chem 276 19687 19690

32. BaskakovIV

LegnameG

BaldwinMA

PrusinerSB

CohenFE

2002 Pathway complexity of prion protein assembly into amyloid. J Biol Chem 277 21140 21148

33. PastranaMA

SajnaniG

OniskoB

CastillaJ

MoralesR

2006 Isolation and characterization of a proteinase K-sensitive PrP(Sc) fraction. Biochemistry 45 15710 15717

34. WestawayD

DeArmondSJ

Cayetano-CanlasJ

GrothD

FosterD

1994 Degeneration of skeletal muscle, peripheral nerves, and the central nervous system in transgenic mice overexpressing wild-type prion proteins. Cell 76 117 129

35. ShmerlingD

HegyiI

FischerM

BlattlerT

BrandnerS

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

36. MuramotoT

DeArmondSJ

ScottM

TellingGC

CohenFE

1997 Heritable disorder resembling neuronal storage disease in mice expressing prion protein with deletion of an α-helix. Nat Med 3 750 755