title: Seeded fibrillation as molecular basis of the species barrier in human prion diseases.
abstract: Prion diseases are transmissible spongiform encephalopathies in humans and animals, including scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, chronic wasting disease (CWD) in deer, and Creutzfeldt-Jakob disease (CJD) in humans. The hallmark of prion diseases is the conversion of the host-encoded prion protein (PrP(C)) to its pathological isoform PrP(Sc), which is accompanied by PrP fibrillation. Transmission is not restricted within one species, but can also occur between species. In some cases a species barrier can be observed that results in limited or unsuccessful transmission. The mechanism behind interspecies transmissibility or species barriers is not completely understood. To analyse this process at a molecular level, we previously established an in vitro fibrillation assay, in which recombinant PrP (recPrP) as substrate can be specifically seeded by PrP(Sc) as seed. Seeding with purified components, with no additional cellular components, is a direct consequence of the "prion-protein-only" hypothesis. We therefore hypothesise, that the species barrier is based on the interaction of PrP(C) and PrP(Sc). Whereas in our earlier studies, the interspecies transmission in animal systems was analysed, the focus of this study lies on the transmission from animals to humans. We therefore combined seeds from species cattle, sheep and deer (BSE, scrapie, CWD) with human recPrP. Homologous seeding served as a control. Our results are consistent with epidemiology, other in vitro aggregation studies, and bioassays investigating the transmission between humans, cattle, sheep, and deer. In contrast to CJD and BSE seeds, which show a seeding activity we can demonstrate a species barrier for seeds from scrapie and CWD in vitro. We could show that the seeding activity and therewith the molecular interaction of PrP as substrate and PrP(Sc) as seed is sufficient to explain the phenomenon of species barriers. Therefore our data supports the hypothesis that CWD is not transmissible to humans.
authors: Institute of Physical Biology, Heinrich-Heine University, Düsseldorf, Germany.
authors: Lars
authors: L
authors: Luers
authors: Oliver
authors: O
authors: Bannach
authors: Jan
authors: J
authors: Stöhr
authors: Michael Marius
authors: MM
authors: Wördehoff
authors: Martin
authors: M
authors: Wolff
authors: Luitgard
authors: L
authors: Nagel-Steger
authors: Detlev
authors: D
authors: Riesner
authors: Dieter
authors: D
authors: Willbold
authors: Eva
authors: E
authors: Birkmann
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D052160:Benzothiazoles; D002417:Cattle; D002942:Circular Dichroism; D003670:Deer; D006801:Humans; D007700:Kinetics; D018620:PrPSc Proteins / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology; D012756:Sheep; D013045:Species Specificity; D013844:Thiazoles / Q000378:metabolism; D014461:Ultracentrifugation
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D018620:PrPSc Proteins; D013844:Thiazoles; C009462:thioflavin T
references: Prion. 2008 Apr-Jun;2(2):67-72
references: 19098436
references: Cell. 2005 Apr 22;121(2):195-206
references: 15851027
references: Science. 2010 Feb 26;327(5969):1132-5
references: 20110469
references: Lancet. 2004 Aug 7-13;364(9433):527-9
references: 15302196
references: Nature. 2001 Jun 14;411(6839):810-3
references: 11459061
references: Emerg Infect Dis. 2006 Oct;12(10):1527-35
references: 17176567
references: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10248-53
references: 10963685
references: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2409-14
references: 18268326
references: Emerg Infect Dis. 2012 Jun;18(6):901-7
references: 22607808
references: Emerg Infect Dis. 2004 Jun;10(6):977-84
references: 15207045
references: Vet Rec. 1991 Mar 2;128(9):199-203
references: 1823120
references: Lancet Neurol. 2005 Oct;4(10):635-42
references: 16168932
references: Protein Eng Des Sel. 2009 Aug;22(8):515-21
references: 19570812
references: J Gen Virol. 2012 Jul;93(Pt 7):1624-1629
references: 22495232
references: Ann Neurol. 1998 Jun;43(6):763-7
references: 9629846
references: Annu Rev Biochem. 1997;66:385-407
references: 9242912
references: J Wildl Dis. 2005 Apr;41(2):275-90
references: 16107661
references: EMBO J. 2000 Sep 1;19(17):4425-30
references: 10970836
references: Haemophilia. 2010 Jul;16 Suppl 5:175-80
references: 20590878
references: Biophys Chem. 1996 Dec 10;63(1):A1-18
references: 8981746
references: PLoS One. 2010 Dec 09;5(12):e14283
references: 21151607
references: Science. 2012 Jan 27;335(6067):472-5
references: 22282814
references: Mol Biotechnol. 1998 Jun;9(3):225-34
references: 9718582
references: J Virol. 2006 Sep;80(18):9104-14
references: 16940522
references: J Biol Chem. 2011 Mar 4;286(9):7490-5
references: 21209079
references: Nat Med. 1998 Oct;4(10):1157-65
references: 9771749
references: PLoS Pathog. 2008 Aug 29;4(8):e1000139
references: 18769716
references: Biochem Biophys Res Commun. 2007 Dec 28;364(4):796-800
references: 17964288
references: Biol Chem. 2006 Jan;387(1):95-102
references: 16497169
references: J Neurosci. 2005 Aug 31;25(35):7944-9
references: 16135751
references: Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15137-42
references: 10611351
references: Science. 2007 Nov 9;318(5852):930-6
references: 17991853
references: Nature. 1997 Oct 2;389(6650):498-501
references: 9333239
references: Nature. 1997 Jul 17;388(6639):285-8
references: 9230438
references: Cell. 2008 Sep 5;134(5):757-68
references: 18775309
references: J Gen Virol. 2010 Oct;91(Pt 10):2651-7
references: 20610667
references: Nat Med. 2011 Feb;17(2):175-8
references: 21278748
references: Biol Chem. 2005 Jun;386(6):569-80
references: 16006244
references: CNS Drugs. 2006;20(1):15-28
references: 16396521
references: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20914-9
references: 18096717
references: Biochem Biophys Res Commun. 2008 Sep 5;373(4):493-7
references: 18585368
references: Nature. 1996 Oct 24;383(6602):685-90
references: 8878476
references: J Virol. 2005 Nov;79(21):13794-6
references: 16227298
references: Arch Virol Suppl. 2000;(16):265-73
references: 11214930
references: PLoS Pathog. 2012;8(6):e1002782
references: 22737075
references: Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9741-6
references: 17535913
references: Lancet. 1996 Apr 6;347(9006):921-5
references: 8598754
references: Science. 2004 Jul 30;305(5684):673-6
references: 15286374
references: Nat Methods. 2008 Mar;5(3):211-2
references: 18309304
references: PLoS One. 2012;7(11):e48969
references: 23139828