title: Prion propagation in mice lacking central nervous system NF-kappaB signalling.
abstract: Prions induce highly typical histopathological changes including cell death, spongiosis and activation of glia, yet the molecular pathways leading to neurodegeneration remain elusive. Following prion infection, enhanced nuclear factor-kappaB (NF-kappaB) activity in the brain parallels the first pathological changes. The NF-kappaB pathway is essential for proliferation, regulation of apoptosis and immune responses involving induction of inflammation. The IkappaB kinase (IKK) signalosome is crucial for NF-kappaB signalling, consisting of the catalytic IKKalpha/IKKbeta subunits and the regulatory IKKgamma subunit. This study investigated the impact of NF-kappaB signalling on prion disease in mouse models with a central nervous system (CNS)-restricted elimination of IKKbeta or IKKgamma in nearly all neuroectodermal cells, including neurons, astrocytes and oligodendrocytes, and in mice containing a non-phosphorylatable IKKalpha subunit (IKKalpha AA/AA). In contrast to previously published data, the observed results showed no evidence supporting the hypothesis that impaired NF-kappaB signalling in the CNS impacts on prion pathogenesis.
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Julius
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Heikenwalder
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Schwarz
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Marcel
authors.affiliation: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, USA.
authors.forename: M
authors.initials: M
authors.lastname: Karin
authors.affiliation: Department of Neuropathology, University of Freiburg, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Institute for Genetics, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Aguzzi
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism* / Q000472:pathogenicity; D012608:Scrapie / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014774:Virulence
chemical_list: D016328:NF-kappa B; D018620:PrPSc Proteins; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse