NR AWFN
AU Giles,K.; Moore,R.; Tremblay,P.; Lataweic,D.; Nguyen,H.O.B.; Bush,C.; DeArmond,S.; Prusiner,S.B.; Legname,G.
TI Mechanism of prion protein rescue of doppel-induced neurodegeneration
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PA-18
PT Konferenz-Poster
AB Doppel (Dpl) is a paralog of the prion protein (PrP). Dpl has been identified in all mammals including marsupials, suggesting ancestral gene duplication at least 140 million years ago. The normal functions of Dpl and PrP are not clearly understood, and their endogenous expression differs markedly. Dpl is predominantly expressed in the testis with little or no expression in the central nervous system (CNS), while PrP is predominantly expressed in the brain. Overexpression of Dpl in the brain, either as a consequence of targeted inactivation of the gene for PrP in certain PrP-deficient mouse lines, or by an exogenous transgene, gives rise to non-transmissible neurodegeneration. Coexpression of PrP in these Dpl-expressing lines has been demonstrated to rescue this phenotype. To identify the mechanism of PrP rescue of Dpl-induced neurodegeneration we developed novel in vivo and in vitro models. We previously showed that increasing Dpl expression in transgenic mice decreased the time to onset of disease. We now demonstrate that recombinant Dpl is neurotoxic to cerebellar granule neurons in vitro in a dose-dependent manner. Systematic in vivo and in vitro studies demonstrated a quantitative dose-dependent relationship for PrP-rescue of Dpl-induced neurotoxicty. This suggests a direct interaction of PrP and Dpl, which we were able to demonstrate in vitro by both surface plasmon resonance and immunoassay. While Dpl is expressed at low levels in the CNS, we could not exclude the possibility that microenvironment concentrations may be high, and that Dpl is involved in prion formation. We therefore developed mice in which Dpl expression was eliminated. These mice had identical incubation periods to wild type mice when inoculated with RML prions, conclusively proving that Dpl does not have a role in prion disease.
AD K. Giles, P. Tremblay, G. Legname: Institute for Neurodegenerative Diseases, Department of Neurology, University of California San Francisco, San Francisco, CA 94143; USA; R. Moore, D. Lataweic, H.-O. Nguyen: Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94143; USA; C. Bush, S. DeArmond: Department of Pathology, University of California San Francisco, San Francisco, CA 94143; USA; S.B. Prusiner: Institute for Neurodegenerative Diseases, Department of Neurology, Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA 94143; USA.
SP englisch
PO Italien