title: Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways.
abstract: Prions induce lethal neurodegeneration and consist of PrPSc, an aggregated conformer of the cellular prion protein PrPC. Antibody-derived ligands to the globular domain of PrPC (collectively termed GDL) are also neurotoxic. Here we show that GDL and prion infections activate the same pathways. Firstly, both GDL and prion infection of cerebellar organotypic cultured slices (COCS) induced the production of reactive oxygen species (ROS). Accordingly, ROS scavenging, which counteracts GDL toxicity in vitro and in vivo, prolonged the lifespan of prion-infected mice and protected prion-infected COCS from neurodegeneration. Instead, neither glutamate receptor antagonists nor inhibitors of endoplasmic reticulum calcium channels abolished neurotoxicity in either model. Secondly, antibodies against the flexible tail (FT) of PrPC reduced neurotoxicity in both GDL-exposed and prion-infected COCS, suggesting that the FT executes toxicity in both paradigms. Thirdly, the PERK pathway of the unfolded protein response was activated in both models. Finally, 80% of transcriptionally downregulated genes overlapped between prion-infected and GDL-treated COCS. We conclude that GDL mimic the interaction of PrPSc with PrPC, thereby triggering the downstream events characteristic of prion infection.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Uli S
authors.initials: US
authors.lastname: Herrmann
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Sonati
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Jeppe
authors.initials: J
authors.lastname: Falsig
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Regina R
authors.initials: RR
authors.lastname: Reimann
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Dametto
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Tracy
authors.initials: T
authors.lastname: O'Connor
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Agnes
authors.initials: A
authors.lastname: Lau
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Simone
authors.initials: S
authors.lastname: Hornemann
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sorce
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Uli
authors.initials: U
authors.lastname: Wagner
authors.affiliation: Department of Pharmacology, Medical School, University of Athens, Athens, Greece.
authors.forename: Despina
authors.initials: D
authors.lastname: Sanoudou
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D018620:PrPSc Proteins / Q000235:genetics / Q000276:immunology*; D017096:Prion Diseases / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D019892:eIF-2 Kinase / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D018620:PrPSc Proteins; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase