NR AXPC
AU Jackson,W.; Borkowski,A.; Faas,H.; Steele,A.; King,O.; Jasanoff,A.; Lindquist,S.
TI Spontaneous Disease in a Knock-in Mouse Model of Prion Disease
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.02
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB Why misfolded proteins are toxic is a central question in neurodegenerative disease research. Compared to studies of prion replication and transmission, less effort has been focused on understanding how prions are toxic. Therefore, we have developed an allelic series of mice to systematically study how mutations to PrP impact its tertiary structure and cause prion disease. Random integration transgene (RIT) mice possess exogenous genes that have integrated into the mouse genome in an unspecified locus, often as multiple copies. Temporal and spatial expression patterns of RITs vary significantly between different lines. Furthermore, some RIT mice expressing wild-type PrP develop disease spontaneously while others do not. For these reasons we used a gene-targeting approach to manipulate the protein coding sequence of the endogenous mouse PrP gene. Our allelic series includes variants expressing point mutations linked to familial prion disease, multiple variants of PrP directly in the cytosol, as well as trafficking mutants, namely N-terminally substituted PrP and disulfide bridge-less PrP. By 18 months of age, mice expressing the mouse equivalent codon responsible for fatal familial insomnia develop a severe neurodegenerative disease detectable by classic histological methods as well as in vivo methods including behavioral assays and magnetic resonance imaging. Lesions are widespread. Surprisingly, these mice show resistance to infection by three strains of prions. We therefore conclude that this mutation can cause disease spontaneously, independent of infection by an exogenous agent. Details of initial transmission experiments of spontaneous prion disease will be presented.
AD W. Jackson, A. Borkowski, A. Steele, O. King, S. Lindquist, Whitehead Institute, USA; H. Faas, A. Jasanoff, Massachusetts Institute of Technology, Francis Bitter Magnet Laboratory, USA
SP englisch
PO Schottland