NR AWBR
AU Baumann,F.; Tolnay,M.; Pahnke,J.; Brabeck,C.; Niemann,H.H.; Ruelicke,T.; Bürkle,A.; Aguzzi,A.
TI In-vivo identification of functional domains within the cellular prion protein
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 CE-02
PT Konferenz-Poster
AB One of the fundamental questions in the field of prion research is whether brain damage during the course of the disease is primarily due to neurotoxicity of the disease associated prion protein (PrPsc), or whether it is due to a loss of function of the cellular form of prion protein PrPc. Very little is known about the physiological function of PrPc. Ablation of PrP in most mouse models does not induce any pathological phenotype. Expression of a prion protein variant lacking amino acids 32-134 (termed PrPF) has been shown to induce neurodegeneration in PrPc-deficient mice, which is rescued by fulllength PrPc. We now report that expression of a PrPc variant lacking the core domain 94-133 (PrPcD) induces a rapidly progressive, lethal phenotype with extensive central and peripheral axomyelinic degeneration. This phenotype was rescued dose-dependently by coexpression of wildtype PrPc, or of PrPc lacking all octarepeats. Expression of a PrPc variant lacking residues 114-121 was innocuous in the presence or absence of wild-type PrPc, yet enhanced the toxicity of PrPcD but not that of PrPF. Therefore, deletion of the core domain generates a strong recessive-negative mutant of PrPc, whereas removal of residues 114-121 creates a partial agonist whose polarity of action is context-dependent. These findings suggest that axomyelinic integrity is maintained by a constitutively active neurotrophic protein complex whose effector encompasses residues 94-133 of PrPc.
AD F. Baumann, M. Tolnay, A. Aguzzi: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland; J. Pahnke: present address: Neurological Clinic, University of Rostock, Rostock, Germany; C. Brabeck: Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany; H.H. Niemann: Division of Tumor Virology, German Cancer Research Center, Heidelberg, Germany; T. Ruelicke: Institute of Laboratory Animal Science and Austrian Center for Biomodels and Transgenetics, University of Veterinary Medicine Vienna, Vienna, Austria; A. Bürkle: Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany, and Division of Tumor Virology, German Cancer Research Center, Heidelberg, Germany. E-mail: adriano.aguzzi@usz.ch
SP englisch
PO Italien