title: Crossing the species barrier by PrP(Sc) replication in vitro generates unique infectious prions.
abstract: Prions are unconventional infectious agents composed exclusively of misfolded prion protein (PrP(Sc)), which transmits the disease by propagating its abnormal conformation to the cellular prion protein (PrP(C)). A key characteristic of prions is their species barrier, by which prions from one species can only infect a limited number of other species. Here, we report the generation of infectious prions by interspecies transmission of PrP(Sc) misfolding by in vitro PMCA amplification. Hamster PrP(C) misfolded by mixing with mouse PrP(Sc) generated unique prions that were infectious to wild-type hamsters, and similar results were obtained in the opposite direction. Successive rounds of PMCA amplification result in adaptation of the in vitro-produced prions, in a process reminiscent of strain stabilization observed upon serial passage in vivo. Our results indicate that PMCA is a valuable tool for the investigation of cross-species transmission and suggest that species barrier and strain generation are determined by the propagation of PrP misfolding.
authors.affiliation: Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Castilla
authors.forename: Dennisse
authors.initials: D
authors.lastname: Gonzalez-Romero
authors.forename: Paula
authors.initials: P
authors.lastname: Saá
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Morales
authors.forename: Jorge
authors.initials: J
authors.lastname: De Castro
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002474:Cell-Free System; D006224:Cricetinae; D051379:Mice; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000473:pathology / Q000635:transmission*; D011328:Prions / Q000378:metabolism*; D017510:Protein Folding; D013045:Species Specificity
chemical_list: D018620:PrPSc Proteins; D011328:Prions
references.citation: J Neurosci Methods. 2007 Sep 30;165(2):183-90
references.pmid: 17644183
references.citation: J Virol. 2007 Sep;81(17):9605-8
references.pmid: 17553879
references.citation: Ciba Found Symp. 1988;135:37-62
references.pmid: 3137002
references.citation: Vet Rec. 1993 Oct 2;133(14):339-41
references.pmid: 8236676
references.citation: Cell. 2005 Apr 8;121(1):49-62
references.pmid: 15820678
references.citation: Nature. 2004 Mar 18;428(6980):323-8
references.pmid: 15029196
references.citation: Nature. 1996 Oct 24;383(6602):685-90
references.pmid: 8878476
references.citation: Arch Virol Suppl. 2005;(19):187-202
references.pmid: 16355873
references.citation: Science. 1982 Apr 9;216(4542):136-44
references.pmid: 6801762
references.citation: Berl Munch Tierarztl Wochenschr. 2005 Sep-Oct;118(9-10):365-71
references.pmid: 16206923
references.citation: Nature. 2004 Mar 18;428(6980):319-23
references.pmid: 15029195
references.citation: J Gen Virol. 1989 Aug;70 ( Pt 8):2017-25
references.pmid: 2504883
references.citation: Acta Vet Scand Suppl. 2003;98:33-42
references.pmid: 15259778
references.citation: J Virol. 2001 Nov;75(21):10106-12
references.pmid: 11581378
references.citation: Cell. 2005 Apr 22;121(2):195-206
references.pmid: 15851027
references.citation: Mol Cell. 2004 Apr 9;14(1):139-45
references.pmid: 15068810
references.citation: Yeast. 1995 Dec;11(16):1671-85
references.pmid: 8720070
references.citation: Trends Neurosci. 2002 Aug;25(8):390-4
references.pmid: 12127750
references.citation: Contrib Microbiol. 2004;11:33-49
references.pmid: 15077403
references.citation: Lancet. 1999 Jul 24;354(9175):317-23
references.pmid: 10440324
references.citation: Annu Rev Neurosci. 2001;24:519-50
references.pmid: 11283320
references.citation: Nature. 2001 Jun 14;411(6839):810-3
references.pmid: 11459061
references.citation: Br Med Bull. 2003;66:99-108
references.pmid: 14522852
references.citation: Vet Microbiol. 2007 Aug 31;123(4):346-57
references.pmid: 17493773
references.citation: EMBO J. 2005 Sep 7;24(17):3082-92
references.pmid: 16096644
references.citation: Nat Methods. 2007 Aug;4(8):645-50
references.pmid: 17643109
references.citation: J Pathol. 2007 Sep;213(1):21-6
references.pmid: 17614097
references.citation: Biochim Biophys Acta. 2007 Jun;1772(6):681-91
references.pmid: 17254754
references.citation: Vet Pathol. 2005 Sep;42(5):530-49
references.pmid: 16145200
references.citation: Nat Med. 2000 Mar;6(3):258-9
references.pmid: 10700223
references.citation: J Biol Chem. 2006 Feb 17;281(7):4199-206
references.pmid: 16338930
references.citation: Neurosci Lett. 2007 Feb 21;413(3):270-3
references.pmid: 17174030
references.citation: Curr Top Microbiol Immunol. 2004;284:133-59
references.pmid: 15148991
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13363-83
references.pmid: 9811807
references.citation: Br Med Bull. 2003;66:171-83
references.pmid: 14522858
references.citation: Mol Biotechnol. 1998 Jun;9(3):225-34
references.pmid: 9718582
references.citation: Nat Med. 2004 Jul;10 Suppl:S63-7
references.pmid: 15272271
references.citation: Neuron. 2002 Jun 13;34(6):854-6
references.pmid: 12086631
references.citation: Nat Med. 1998 Oct;4(10):1157-65
references.pmid: 9771749
references.citation: J Biol Chem. 2005 Jul 22;280(29):26873-9
references.pmid: 15917229
references.citation: J Biochem Biophys Methods. 2005 Jun 30;63(3):213-21
references.pmid: 15967508
references.citation: Arch Virol Suppl. 2000;(16):209-16
references.pmid: 11214924
references.citation: FEBS Lett. 2005 Jan 31;579(3):638-42
references.pmid: 15670821
references.citation: Biochim Biophys Acta. 2007 Jun;1772(6):610-8
references.pmid: 17223321
references.citation: Methods Mol Biol. 2005;299:53-65
references.pmid: 15980595
references.citation: J Infect Dis. 2002 Dec 1;186 Suppl 2:S166-70
references.pmid: 12424693
references.citation: Methods Enzymol. 2006;412:3-21
references.pmid: 17046648
references.citation: CNS Drugs. 2006;20(1):15-28
references.pmid: 16396521
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9741-6
references.pmid: 17535913
references.citation: Lancet. 1996 Apr 6;347(9006):921-5
references.pmid: 8598754