title: The role of the NADPH oxidase NOX2 in prion pathogenesis.
abstract: Prion infections cause neurodegeneration, which often goes along with oxidative stress. However, the cellular source of reactive oxygen species (ROS) and their pathogenetic significance are unclear. Here we analyzed the contribution of NOX2, a prominent NADPH oxidase, to prion diseases. We found that NOX2 is markedly upregulated in microglia within affected brain regions of patients with Creutzfeldt-Jakob disease (CJD). Similarly, NOX2 expression was upregulated in prion-inoculated mouse brains and in murine cerebellar organotypic cultured slices (COCS). We then removed microglia from COCS using a ganciclovir-dependent lineage ablation strategy. NOX2 became undetectable in ganciclovir-treated COCS, confirming its microglial origin. Upon challenge with prions, NOX2-deficient mice showed delayed onset of motor deficits and a modest, but significant prolongation of survival. Dihydroethidium assays demonstrated a conspicuous ROS burst at the terminal stage of disease in wild-type mice, but not in NOX2-ablated mice. Interestingly, the improved motor performance in NOX2 deficient mice was already measurable at earlier stages of the disease, between 13 and 16 weeks post-inoculation. We conclude that NOX2 is a major source of ROS in prion diseases and can affect prion pathogenesis.
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sorce
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Mario
authors.initials: M
authors.lastname: Nuvolone
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Annika
authors.initials: A
authors.lastname: Keller
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: Ahmet
authors.initials: A
authors.lastname: Varol
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Schwarz
authors.affiliation: Institute of Surgical Pathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Bieri
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Herbert
authors.initials: H
authors.lastname: Budka
authors.affiliation: Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D049109:Cell Proliferation; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011328:Prions / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D011328:Prions; D017382:Reactive Oxygen Species; C056558:CYBB protein, human; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases