NR AWGK
AU Harris,D.A.; Stewart,L.; Christensen,H.M.; Roth,K.A.; Chiesa,R.; Li,A.
TI Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105-125
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-28
PT Konferenz-Vortrag
AB PrPc possesses neuroprotective properties, but deletion of specific regions of the molecule is known to unmask neurotoxic activities of the protein. To identify domains of PrP important for its neurotoxic and neuroprotective properties, we have engineered transgenic mice that express a form of murine PrP deleted for a conserved block of 21 amino acids (residues 105-125) in the unstructured, N-terminal tail of the protein. These mice spontaneously developed a severe neurodegenerative illness that was lethal within 1 week of birth on the Prn-p0/0 (PrP-null) background. This phenotype was reversed in a dose-dependent fashion by co-expression of wild-type PrP, with endogenous levels of wild-type protein (Prn-p+/+ background) delaying death until 30-60 days, and 5X over-expression of wild-type protein (produced by introduction of a Tga20 transgene) delaying death beyond 1 year. The phenotype of Tg(PrP105-125) mice is reminiscent of, but much more severe than, those described in mice that express PrP harboring larger deletions of the N-terminus (32-121 and 32-134) (Shmerling et al., Cell 93:203-214, 1998), and in mice that ectopically express Doppel, a PrP paralog, in the CNS (Rossi et al., EMBO J. 20:694-702, 2001). The dramatically increased specific toxicity of PrP105-125 is most consistent with a model in which this protein has greatly enhanced affinity for a hypothetical receptor that serves to transduce the toxic signal. Our results define the region encompassing residues 105-125 as a crucial determinant of the neurotoxic and neuroprotective activities of PrP, and they suggest new models for how the physiological function of PrPc might be subverted to generate neurotoxic signals during prion infection and after exposure to the toxic peptide PrP106-126.
AD D.A. Harris, L. Stewart, H.M. Christensen, A. Li: Dept. of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; K.A. Roth: Dept. of Pathology, University of Alabama at Birmingham (UAB), Birmingham, AL 35294, USA; R. Chiesa: Dulbecco Telethon Institute (DTI) and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, Milano, 20157, Italy. E-mail: dharris@wustl.edu
SP englisch
PO Italien