title: Neurodegeneration and unfolded-protein response in mice expressing a membrane-tethered flexible tail of PrP.
abstract: The cellular prion protein (PrPC) consists of a flexible N-terminal tail (FT, aa 23-128) hinged to a membrane-anchored globular domain (GD, aa 129-231). Ligation of the GD with antibodies induces rapid neurodegeneration, which is prevented by deletion or functional inactivation of the FT. Therefore, the FT is an allosteric effector of neurotoxicity. To explore its mechanism of action, we generated transgenic mice expressing the FT fused to a GPI anchor, but lacking the GD (PrPΔ141-225, or "FTgpi"). Here we report that FTgpi mice develop a progressive, inexorably lethal neurodegeneration morphologically and biochemically similar to that triggered by anti-GD antibodies. FTgpi was mostly retained in the endoplasmic reticulum, where it triggered a conspicuous unfolded protein response specifically activating the PERK pathway leading to phosphorylation of eIF2α and upregulation of CHOP ultimately leading to neurodegeration similar to what was observed in prion infection.
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Paolo
authors: P
authors: Dametto
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Asvin K K
authors: AK
authors: Lakkaraju
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Claire
authors: C
authors: Bridel
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Lukas
authors: L
authors: Villiger
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Tracy
authors: T
authors: O'Connor
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Uli S
authors: US
authors: Herrmann
authors: Institute of Laboratory Animal Science, University of Zürich, Zurich, Switzerland.
authors: Pawel
authors: P
authors: Pelczar
authors: Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Rülicke
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Donal
authors: D
authors: McHugh
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Arlind
authors: A
authors: Adili
authors: Institute of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Adriano
authors: A
authors: Aguzzi
mesh_terms: D000818:Animals; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D051379:Mice; D008822:Mice, Transgenic; D018621:PrPC Proteins / Q000032:analysis / Q000378:metabolism*; D017096:Prion Diseases / Q000378:metabolism* / Q000473:pathology*; D011328:Prions; D056811:Unfolded Protein Response
chemical_list: D018621:PrPC Proteins; D011328:Prions