Cell-free propagation of prion strains.
Prions are the infectious agents responsible for prion diseases, which appear to be composed exclusively by the misfolded prion protein (PrP(Sc)). Disease is transmitted by the autocatalytic propagation of PrP(Sc) misfolding at the expense of the normal prion protein. The biggest challenge of the prion hypothesis has been to explain the molecular mechanism by which prions can exist as different strains, producing diseases with distinguishable characteristics. Here, we show that PrP(Sc) generated in vitro by protein misfolding cyclic amplification from five different mouse prion strains maintains the strain-specific properties. Inoculation of wild-type mice with in vitro-generated PrP(Sc) caused a disease with indistinguishable incubation times as well as neuropathological and biochemical characteristics as the parental strains. Biochemical features were also maintained upon replication of four human prion strains. These results provide additional support for the prion hypothesis and indicate that strain characteristics can be faithfully propagated in the absence of living cells, suggesting that strain variation is dependent on PrP(Sc) properties.
Castilla
Joaquín
J
Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Morales
Rodrigo
R
Saá
Paula
P
Barria
Marcelo
M
Gambetti
Pierluigi
P
Soto
Claudio
C
D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D002474:Cell-Free System; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018620:PrPSc Proteins / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014020:Tissue Extracts / Q000378:metabolism
D018620:PrPSc Proteins; D020033:Protein Isoforms; D014020:Tissue Extracts
Nature. 2004 Mar 18;428(6980):319-23
15029195
Science. 1998 Jan 2;279(5347):42-3
9441410
Br Med Bull. 2003;66:1-20
14522845
Biochim Biophys Acta. 2007 Jun;1772(6):681-91
17254754
J Comp Pathol. 1973 Jan;83(1):29-40
4199908
Nat Rev Mol Cell Biol. 2007 Jul;8(7):552-61
17585315
Nature. 1998 Jan 22;391(6665):345-6
9450747
Methods Mol Biol. 2005;299:53-65
15980595
Nature. 1996 Oct 24;383(6602):685-90
8878476
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9741-6
17535913
J Virol. 2005 Aug;79(16):10796-806
16051871
Cell. 2005 Apr 22;121(2):195-206
15851027
Annu Rev Biochem. 2004;73:617-56
15189155
Yeast. 1995 Dec;11(16):1671-85
8720070
Trends Neurosci. 2002 Aug;25(8):390-4
12127750
Br Med Bull. 2003;66:213-39
14522861
Annu Rev Neurosci. 2001;24:519-50
11283320
J Vet Med B Infect Dis Vet Public Health. 2005 Mar;52(2):55-63
15752263
Nature. 2001 Jun 14;411(6839):810-3
11459061
Br Med Bull. 2003;66:99-108
14522852
Vet Microbiol. 2007 Aug 31;123(4):346-57
17493773
Science. 1996 Dec 20;274(5295):2079-82
8953038
EMBO J. 2005 Sep 7;24(17):3082-92
16096644
J Biol Chem. 2006 Nov 17;281(46):35245-52
16982620
J Gen Virol. 1991 Mar;72 ( Pt 3):595-603
1672371
J Virol. 1992 Apr;66(4):2096-101
1347795
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
9811807
Nat Med. 2004 Jul;10 Suppl:S63-7
15272271
Nat Med. 1998 Oct;4(10):1157-65
9771749
Cold Spring Harb Symp Quant Biol. 2004;69:489-96
16117685
Trends Biochem Sci. 2002 Dec;27(12):606-12
12468229
Trends Microbiol. 2000 Apr;8(4):157-8
10754572
Arch Virol Suppl. 2000;(16):209-16
11214924
FEBS Lett. 2005 Jan 31;579(3):638-42
15670821
Annu Rev Microbiol. 2002;56:703-41
12142498
Nature. 1991 Aug 22;352(6337):679-83
1876183
Nat Rev Microbiol. 2004 Nov;2(11):861-71
15494743
Brain. 2003 Jun;126(Pt 6):1333-46
12764055
Methods Enzymol. 2006;412:3-21
17046648
Sci Prog. 1976 Winter;63(252):461-81
823641
Nature. 2004 Mar 18;428(6980):323-8
15029196
J Gen Virol. 2002 Mar;83(Pt 3):695-704
11842264
J Biol Chem. 1998 Nov 27;273(48):32230-5
9822701
Philos Trans R Soc Lond B Biol Sci. 1994 Mar 29;343(1306):413-4
7913759
Science. 2004 Jul 30;305(5684):673-6
15286374
Philos Trans R Soc Lond B Biol Sci. 1994 Mar 29;343(1306):425-30
7913761