NR AUQW
AU Watts,J.C.; Drisaldi,B.; Yang,J.; Strome,B.; Horne,P.; Fraser,P.E.; Mount,H.T.J.; Schmitt-Ulms,G.; Westaway,D.
TI Functional Analysis of Mammalian Prion Proteins: Shadoo and PrPc have overlapping activities
QU TSE-Forum, 6. Kongress - Nationale TSE-Forschungsplattform, Greifswald 26.6.-28.6.2006, Vortrag V-15
PT Konferenz-Vortrag
AB Two cellular prion proteins are currently known: the PrPsc precursor denoted PrPc and a Doppelänger (Doppel), a molecule with a similar three-dimensional structure expressed outside of the central nervous system. While PrPc's mechanism of action is debated, a neuroprotective effect is apparent in several settings. Building upon a particularly well-documented paradigm - protection against the neurotoxic action of Doppel and mutant forms of PrP ("deltaPrP") expressed in the CNS - we have mapped two functional determinants in a central, unstructured region of mouse PrP. Two additional determinants, most likely targeting signals, lie within an N-terminal charged region and the copper-binding octarepeats. Here we demonstrate that the notional Shadow locus (Shadoo, "Sho") identified by genomic sequencing encodes a glycoprotein that is expressed in the mouse brain from late embryonic life. Like PrP, Sho is GPI-anchored. Sho shares greatest sequence homology to the central natively unfolded region of PrP and, remarkably, when expressed in cerebellar granule cell neurons is also neuroprotective against the toxic action of doppel. These data suggest that Sho corresponds to the PrP-like "pi" molecule hypothesized by Weissmann and co-workers [Shmerling et al., Cell 93:203-214, 1998]. Conservation of an ancient activity domain in cellular prion proteins - a domain that coincides with the epicenter of misfolding to disease-associated forms such as PrPsc - implies that the physiology and pathogenic potential of cellular prion proteins are closely intertwined.
AD Joel C. Watts, Bettina Drisaldi, Jing Yang, Bob Strome, Patrick Horne, Paul E. Fraser, Howard T.J. Mount, Gerold Schmitt-Ulms, David Westaway, Centre for Research in Neurodegenerative Diseases; Joel C. Watts, Gerold Schmitt-Ulms, David Westaway, Department of Laboratory Medicine and Pathobiology; Paul E. Fraser, Department of Medical Biophysics; Howard T.J. Mount, Department of Medicine, University of Toronto, Canada
SP englisch
PO Deutschland
OR Tagungsband