title: Dissociation of prion protein amyloid seeding from transmission of a spongiform encephalopathy.
abstract: Misfolding and aggregation of proteins are common pathogenic mechanisms of a group of diseases called proteinopathies. The formation and spread of proteinaceous lesions within and between individuals were first described in prion diseases and proposed as the basis of their infectious nature. Recently, a similar "prion-like" mechanism of transmission has been proposed in other neurodegenerative diseases such as Alzheimer's disease. We investigated if misfolding and aggregation of corrupted prion protein (PrP(TSE)) are always associated with horizontal transmission of disease. Knock-in transgenic mice (101LL) expressing mutant PrP (PrP-101L) that are susceptible to disease but do not develop any spontaneous neurological phenotype were inoculated with (i) brain extracts containing PrP(TSE) from healthy 101LL mice with PrP plaques in the corpus callosum or (ii) brain extracts from mice overexpressing PrP-101L with neurological disease, severe spongiform encephalopathy, and formation of proteinase K-resistant PrP(TSE). In all instances, 101LL mice developed PrP plaques in the area of inoculation and vicinity in the absence of clinical disease or spongiform degeneration of the brain. Importantly, 101LL mice did not transmit disease on serial passage, ruling out the presence of subclinical infection. Thus, in both experimental models the formation of PrP(TSE) is not infectious. These results have implications for the interpretation of tests based on the detection of protein aggregates and suggest that de novo formation of PrP(TSE) in the host does not always result in a transmissible prion disease. In addition, these results question the validity of assuming that all diseases due to protein misfolding can be transmitted between individuals.
authors.affiliation: Laboratory of Bacterial and TSE Agents, Food and Drug Administration, Kensington, Maryland, USA.
authors.forename: Pedro
authors.initials: P
authors.lastname: Piccardo
authors.forename: Declan
authors.initials: D
authors.lastname: King
authors.forename: Glenn
authors.initials: G
authors.lastname: Telling
authors.forename: Jean C
authors.initials: JC
authors.lastname: Manson
authors.forename: Rona M
authors.initials: RM
authors.lastname: Barron
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000821:virology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D011328:Prions / Q000235:genetics / Q000378:metabolism*
chemical_list: D000682:Amyloid; D011328:Prions
references.citation: J Virol. 2003 Jul;77(13):7611-22
references.pmid: 12805461
references.citation: J Neurochem. 2008 Jun 1;105(6):2190-204
references.pmid: 18298665
references.citation: J Biol Chem. 2012 Aug 31;287(36):30205-14
references.pmid: 22807452
references.citation: Science. 2010 Feb 26;327(5969):1132-5
references.pmid: 20110469
references.citation: PLoS Pathog. 2011 Jul;7(7):e1002128
references.pmid: 21779169
references.citation: Nature. 2001 Jun 14;411(6839):810-3
references.pmid: 11459061
references.citation: Biochemistry. 2010 May 11;49(18):3928-34
references.pmid: 20377181
references.citation: EMBO J. 2005 Jul 6;24(13):2472-80
references.pmid: 15962001
references.citation: J Gen Virol. 1999 Jan;80 ( Pt 1):11-14
references.pmid: 9934677
references.citation: J Infect Dis. 2002 Dec 1;186 Suppl 2:S166-70
references.pmid: 12424693
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20914-9
references.pmid: 18096717
references.citation: Cell. 1983 Nov;35(1):57-62
references.pmid: 6414721
references.citation: Nat Rev Neurosci. 2010 Mar;11(3):155-9
references.pmid: 20029438
references.citation: Brain Pathol. 2012 Jan;22(1):58-66
references.pmid: 21645162
references.citation: Science. 1982 Apr 9;216(4542):136-44
references.pmid: 6801762
references.citation: Nat Methods. 2008 Mar;5(3):211-2
references.pmid: 18309304
references.citation: J Cell Biochem. 2011 Dec;112(12):3630-7
references.pmid: 21793041
references.citation: EMBO J. 1999 Dec 1;18(23):6855-64
references.pmid: 10581259
references.citation: Science. 2012 Jan 27;335(6067):472-5
references.pmid: 22282814
references.citation: Nature. 2005 Sep 8;437(7056):257-61
references.pmid: 16148934
references.citation: Trends Mol Med. 2010 Nov;16(11):501-7
references.pmid: 20870462
references.citation: Science. 2005 Jun 3;308(5727):1435-9
references.pmid: 15933194
references.citation: J Biol Chem. 2007 Dec 7;282(49):35878-86
references.pmid: 17923484
references.citation: J Neurosci. 2008 Dec 3;28(49):13258-67
references.pmid: 19052217
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8322-7
references.pmid: 9653185
references.citation: Acta Neuropathol. 2010 Feb;119(2):177-87
references.pmid: 20052481
references.citation: Science. 1997 Jan 17;275(5298):402-5
references.pmid: 8994041
references.citation: Nature. 1967 Dec 30;216(5122):1310-1
references.pmid: 5625087
references.citation: J Gen Virol. 1996 Aug;77 ( Pt 8):1925-34
references.pmid: 8760444
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4712-7
references.pmid: 17360589
references.citation: J Neuropathol Exp Neurol. 1998 Oct;57(10):979-88
references.pmid: 9786248
references.citation: J Virol. 2012 Nov;86(21):11763-78
references.pmid: 22915801
references.citation: J Virol. 2011 Feb;85(3):1174-81
references.pmid: 21084466
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):E1244-53
references.pmid: 22065744
references.citation: Am J Pathol. 1995 Aug;147(2):503-15
references.pmid: 7639340
references.citation: Nat Rev Mol Cell Biol. 2010 Apr;11(4):301-7
references.pmid: 20308987
references.citation: J Gen Virol. 2011 Feb;92(Pt 2):467-76
references.pmid: 20943888
references.citation: Biochemistry. 2002 Oct 22;41(42):12868-75
references.pmid: 12379130
references.citation: Neuron. 2012 Feb 23;73(4):685-97
references.pmid: 22365544