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The molecular basis for transmission of human prion strains
Author(s) -
Giles Kurt,
Patel Smita,
De Nicola Gian,
Korth Carston,
Lemus Azucena,
DeArmond Stephen,
Prusiner Stanley B
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.850.2
Subject(s) - strain (injury) , prion protein , biology , virology , genetically modified mouse , bovine spongiform encephalopathy , transmission (telecommunications) , transgene , disease , genetics , gene , medicine , pathology , anatomy , electrical engineering , engineering
Human prion diseases, such as Creutzfeldt‐Jakob disease (CJD), can occur in different "strains" which are characterized by their clinical onset, and by biochemical and neuropathological hallmarks of the post mortem brain. Human prion strain type is dramatically influenced by the M/V polymorphism at residue 129, with homozygous individuals much more likely to develop disease. We report a series of novel transgenic (Tg) mouse lines expressing various chimeras of mouse and human prion protein (PrP), which were inoculated with either of the two most common strains of sporadic (s) CJD, termed MM1 and VV2, or with the variant (v) CJD strain. The differential susceptibility for each strain allows a molecular dissection of the amino acid residues that influence strain propagation. One Tg line was susceptibility to sCJD(MM1) prions in less than 80 days, and defined six human PrP residues in the central region of the molecule that are essential for strain transmission. Conversely, for the sCJD(VV2) strain, transmission is regulated by residues in the terminal regions of the PrP sequence. Modification of strain characteristics on transmission of sCJD(VV2) and vCJD strains, also allowed us to formulate a general set of rules governing strain transformation.