NR AXXJ
AU Tamgüney,G.; Giles,K.; Glidden,D.V.; Lessard,P.; Wille,H.; Legname,G.; Tremblay,P.; Groth,D.F.; Yehiely,F.; Korth,C.; Moore,R.C.; Tatzelt,J.; Rubenstein,E.; Boucheix,C.; Lisanti,M.P.; Dwek,R.A.; Rudd,P.M.; Sisodia,S.S.; Moskovitz,J.; Epstein,R.J.; Dawson Cruz,T.C.; Kuziel,W.A.; Maeda,N.; Pagoulatos,G.N.; Sap,J.; Ashe,K.H.; Carlson,G.A.; Tesseur,I.; Wyss-Coray,T.; Mucke,L.; Mahley,R.W.; Cohen,F.E.; Prusiner,S.B.
TI A Search for Auxiliary Proteins in Prion Replication
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Protein Misfolding P01.62
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Poster
AB
Background: Prion diseases in humans and animals are caused by conversion of a normally folded, nonpathogenic isoform (PrPc) of the prion protein to a misfolded, pathogenic isoform (PrPsc) that is transmissible. Genetic experiments have shown that the conversion reaction involves as-yet unidentified protein cofactors. The ultimate proof of the identity of a conversion cofactor, or protein X, is the substantial decrease in susceptibility, or even resistance, to prion infection in animals in which protein X expression has been ablated. Alternatively, transgenic overexpression of protein X should lead to an accelerated onset of prion disease. Many proteins that are upregulated in prion disease or relevant to other neurodegenerative disorders, such as Alzheimer's disease (AD), have been proposed as possible modulators of the prion incubation time; however, the identity of protein X remains elusive.
Aim: In our search for protein X, we analyzed the effect of 21 genes in a large number of mouse models on the incubation time after infection with prions. Among these were genes associated with AD, inflammation, signaling, protein expression, cycling, and maintenance.
Methods: Mice in which the gene of interest was ablated or transgenically overexpressed were inoculated with mouse-adapted prions and the times until onset of neurologic symptoms were measured.
Results: Most genes tested here did not significantly affect incubation times in the respective mouse model after infection with prions. However, we identified the Interleukin 1 receptor, type I (Il1r1) as a significant modifier of prion incubation time, with Il1r1 knockout mice living 13% longer than wild-type mice.
Conclusion: Although Il1r1 showed a statistically significant influence on the incubation time, incubation times in prion-inoculated Il1r1-/-mice were only minimally longer than in inoculated wild-type mice, thus making it unlikely that Il1r1 is protein X. While some of the genes tested here may have a role in the normal function of PrPc, this work clearly shows that many genes formerly implicated as potential auxiliary proteins in prion replication have no discernable effect on prion disease. Thus, we conclude that they are unlikely to be protein X.
AD G. Tamguney, K. Giles, P. Lessard, H. Wille, G. Legname, P. Tremblay, D.F. Groth, F. Yehiely, C. Korth, R.C. Moore, J. Tatzelt, F.E. Cohen, S.B. Prusiner, UCSF, IND, USA; D.V. Glidden, UCSF, Epidemiology and Biostatistics, USA; E. Rubenstein, C. Boucheix, INSERM, U602 and Université Paris, France; M.P. Lisanti, Albert Einstein College of Medicine, USA; R.A. Dwek, P.M. Rudd, University of Oxford, UK; S.S. Sisodia, The University of Chicago, USA; J. Moskovitz, University of Kansas, USA; R.J. Epstein, UCSF, USA; T.C. Dawson Cruz, W.A. Kuziel, N. Maeda, The University of North Carolina Medical Center, USA; G.N. Pagoulatos, University of Ioannina, Medical School, Greece; J. Sap, NYU School of Medicine, USA; K.H. Ashe, University of Minnesota, USA; G.A. Carlson, McLaughlin Research Institute, USA; I. Tesseur, T. Wyss-Coray, Stanford University, USA; L. Mucke, Gladstone Institute of Neurological Disease, USA; R.W. Mahley, Gladstone Institutes of Neurological Disease and Cardiovascular Disease, USA
SP englisch
PO Schottland